U.S. patent number 10,752,617 [Application Number 16/297,115] was granted by the patent office on 2020-08-25 for indazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ror gamma (t)).
This patent grant is currently assigned to GALDERMA RESEARCH & DEVELOPMENT. The grantee listed for this patent is GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Claire Bouix-Peter, Branislav Musicki, Gilles Ouvry, Etienne Thoreau.
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United States Patent |
10,752,617 |
Musicki , et al. |
August 25, 2020 |
Indazole sulfonamide derivatives as inverse agonists of
retinoid-related orphan receptor gamma (ROR gamma (T))
Abstract
Indazole sulfonamide derivatives of formula (I), the
pharmaceutically acceptable addition salts thereof, the hydrates
and/or solvates thereof, and the use of same as inverse agonists of
retinoid-related orphan receptor gamma ROR.gamma.t are described.
Pharmaceutical compositions including such compounds, as well as
the use thereof for the topical and/or oral treatment of
ROR.gamma.t receptor-mediated inflammatory diseases, in particular
acne, psoriasis and/or atopic dermatitis are also described.
Inventors: |
Musicki; Branislav (Nice,
FR), Ouvry; Gilles (Biot, FR), Thoreau;
Etienne (Saint Vallier de Thiey, FR), Bouix-Peter;
Claire (Vallauris, FR) |
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA RESEARCH & DEVELOPMENT |
Biot |
N/A |
FR |
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Assignee: |
GALDERMA RESEARCH &
DEVELOPMENT (Biot, FR)
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Family
ID: |
52779811 |
Appl.
No.: |
16/297,115 |
Filed: |
March 8, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190202819 A1 |
Jul 4, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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15537678 |
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10246440 |
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PCT/EP2015/080689 |
Dec 18, 2015 |
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Foreign Application Priority Data
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Dec 19, 2014 [FR] |
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14 63035 |
Jul 3, 2015 [FR] |
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15 56341 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
17/04 (20180101); C07D 209/34 (20130101); C07D
409/06 (20130101); C07D 405/12 (20130101); C07D
307/79 (20130101); C07D 215/36 (20130101); C07D
405/04 (20130101); C07D 403/06 (20130101); C07D
405/06 (20130101); C07D 407/04 (20130101); C07D
401/06 (20130101); C07D 409/04 (20130101); C07D
471/10 (20130101); A61P 17/10 (20180101); C07D
401/14 (20130101); C07D 235/26 (20130101); C07D
403/04 (20130101); C07D 401/04 (20130101); A61P
17/06 (20180101); C07D 417/06 (20130101); C07D
413/06 (20130101); C07D 405/14 (20130101); C07D
231/56 (20130101) |
Current International
Class: |
C07D
231/56 (20060101); C07D 405/14 (20060101); C07D
401/04 (20060101); C07D 403/06 (20060101); C07D
407/04 (20060101); C07D 409/04 (20060101); C07D
409/06 (20060101); C07D 417/06 (20060101); C07D
471/10 (20060101); C07D 209/34 (20060101); C07D
405/12 (20060101); C07D 405/06 (20060101); C07D
405/04 (20060101); C07D 403/04 (20060101); C07D
401/06 (20060101); C07D 215/36 (20060101); C07D
401/14 (20060101); C07D 235/26 (20060101); C07D
413/06 (20060101); A61P 17/04 (20060101); A61P
17/06 (20060101); A61P 17/10 (20060101); A61K
31/416 (20060101); C07D 307/79 (20060101) |
Field of
Search: |
;548/361.1,358.1
;514/412 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO-2006/052190 |
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May 2006 |
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WO |
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WO-2011/137089 |
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Nov 2011 |
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WO |
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WO-2013/160418 |
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Oct 2013 |
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WO |
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WO-2014/090712 |
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Jun 2014 |
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WO |
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Other References
International Search Report dated Mar. 7, 2016 corresponding to
International Patent Application No. PCT/EP2015/080689, 6 pages.
cited by applicant .
Zhang et al., "Discovery of 2-oxo-1,
2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new RORy
inhibitors using virtual screening, synthesis and biological
evaluation", European J. Med. Chem., vol. 78, Mar. 2014, pp.
431-444, XP028847891. cited by applicant .
Chemical Abstracts Registry No. 1328091-23-1, indexed in the
Registry file on STN CAS Online on Sep. 4, 2011. (Year : 2011).
cited by applicant .
Chemical Abstracts Registry No. 914244-66-9, indexed in the
Registry file on STN CAS Online on Nov. 29, 2006. (Year : 2006).
cited by applicant .
Chemical Abstracts Registry No. 924168-33-2, indexed in the
Registry file on STN CAS Online on Mar. 1, 2007. (Year: 2007).
cited by applicant .
Chemical Abstracts Registry No. 950052-33-2, indexed in the
Registry file on STN CAS Online on Oct. 10, 2007. (Year : 2007).
cited by applicant.
|
Primary Examiner: Balasubramanian; Venkataraman
Attorney, Agent or Firm: Foley & Lardner LLP Talapatra;
S.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No.
15/537,678, filed Jun. 19, 2017, which is the National Stage of
PCT/EP2015/080689, filed Dec. 18, 2015, published on Jun. 23, 2016
as WO 2016/097391 A1, which claims priority to French Application
No. 1463035, filed Dec. 19, 2014 and to French Application No.
1556341, filed Jul. 3, 2015. The contents of these applications are
herein incorporated by reference in their entirety.
Claims
The invention claimed is:
1. A compound of formula (II), or a pharmaceutically acceptable
salt thereof, a hydrate thereof, or a solvate thereof: ##STR00296##
wherein: one or two of the elements Y.sup.1, Y.sup.2, Y.sup.3,
Y.sup.4 and Y.sup.5 represent(s) a nitrogen atom and the other
elements correspond to a group --CR.sup.2, or each of the elements
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 corresponds to a
group --CR.sup.2, R.sup.1 represents a linear or branched
C.sub.3-C.sub.5 alkyl radical, optionally substituted with a
hydroxyl group and/or a halogen atom, a C.sub.3-C.sub.5 cycloalkyl
radical, a --CH.sub.2--(C.sub.3-C.sub.5)cycloalkyl radical, or a
--CH.sub.2--(C.sub.4-C.sub.6)heterocycloalkyl radical, R.sup.2
represents a hydrogen atom or a halogen atom, a linear or branched
C.sub.1-C.sub.5 alkyl radical, a C.sub.1-C.sub.4 alkoxy radical, a
cyano group --CN, or a radical --C(.dbd.O)R'.sup.2 with R'.sup.2
denoting a C.sub.1-C.sub.3 alkoxy radical, or a --CF.sub.3 radical;
said alkyl, alkenyl and alkoxy radicals optionally being
substituted with one or more halogen atoms, R.sup.3 represents a
hydrogen atom, a halogen atom, or a group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7 or a
group CH.dbd.R.sup.7, n and o are zero, p is zero or 1, R'.sup.6
represent a hydrogen atom, R.sup.7 represents: a heterocycloalkyl
radical, wherein the heterocycloalkyl radical is optionally
substituted with one or more halogen atoms, one or more linear or
branched C.sub.1-C.sub.3 alkyl groups, one or more --OH groups, one
or more carbonyl functions, one or more linear or branched
C.sub.1-C.sub.4 hydroxyalkyl groups, one or more amino groups, one
or more groups --C(.dbd.O)R.sup.7a, or one or more groups
S(.dbd.O).sub.2R.sup.7a; R.sup.7a representing a linear or branched
C.sub.1-C.sub.3 alkyl radical, a linear or branched C.sub.1-C.sub.3
alkoxy radical, or an amino radical N(R.sup.8a)(R.sup.8b), an
aromatic radical, wherein the aromatic radical is optionally
substituted with one or more halogen atoms, one or more linear or
branched C.sub.1-C.sub.3 alkyl groups optionally substituted with
one or more halogen atoms, one or more C.sub.1-C.sub.3 alkoxy
groups, one or more amino groups --NR.sup.11R.sup.12, one or more
groups --COR.sup.11, one or more groups --COOR.sup.11, one or more
amido groups CONR.sup.11R.sup.12, one or more groups --SOR.sup.11,
one or more groups --SO.sub.2R.sup.11, one or more groups
--NHCOR.sup.11, one or more groups --NHCOOR.sup.11, one or more
groups --SO.sub.2NR.sup.11R.sup.12 or one or more CN groups;
R.sup.11 and R.sup.12, which are identical or different,
representing a hydrogen atom, a hydroxyl radical --OH, or a linear
or branched C.sub.1-C.sub.3 alkyl radical optionally substituted
with one or more halogen atoms; or a heteroaromatic radical,
wherein the heteroaromatic radical is optionally substituted with
one or more halogen atoms, one or more linear or branched
C.sub.1-C.sub.3 alkyl groups optionally substituted with one or
more halogen atoms, one or more C.sub.1-C.sub.3 alkoxy groups, one
or more amino groups --NR.sup.11R.sup.12, one or more groups
--COR.sup.11, one or more groups --COOR.sup.11, one or more amido
groups CONR.sup.11R.sup.12, one or more groups --SOR.sup.11, one or
more groups --SO.sub.2R.sup.11, one or more groups --NHCOR.sup.11,
one or more groups --NHCOOR.sup.11, one or more groups
--SO.sub.2NR.sup.11R.sup.12 or one or more CN groups; R.sup.11 and
R.sup.12, which are identical or different, representing a hydrogen
atom, a hydroxyl radical --OH, or a linear or branched
C.sub.1-C.sub.3 alkyl radical optionally substituted with one or
more halogen atoms; R.sup.5 represents a hydrogen atom, a linear or
branched C.sub.1-C.sub.3 alkyl radical optionally substituted with
one or more halogen atoms; an amino radical --NH.sub.2, an
OCH.sub.2--(C.sub.4-C.sub.5) heterocyclic radical, or a radical
CH.sub.2R'.sup.7a with R'.sup.7a denoting a hydroxyl group --OH
function, and R.sup.8a and R.sup.8b, which are identical or
different, denote a hydrogen atom, a linear or branched
C.sub.1-C.sub.3 alkyl radical or a cyclopropyl radical.
2. A compound of formula (III), or a pharmaceutically acceptable
salt thereof, a hydrate thereof, or a solvate thereof: ##STR00297##
wherein: one or two of the elements Y.sup.1, Y.sup.2, Y.sup.3,
Y.sup.4 and Y.sup.5 represent(s) a nitrogen atom and the other
elements correspond to a group --CR.sup.2, or each of the elements
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 corresponds to a
group --CR.sup.2, R.sup.1 represents a linear or branched
C.sub.3-C.sub.5 alkyl radical, optionally substituted with a
hydroxyl group and/or a halogen atom, a C.sub.3-C.sub.5 cycloalkyl
radical, a linear or branched C.sub.2-C.sub.5 alkenyl radical, a
--CH.sub.2--(C.sub.3-C.sub.5)cycloalkyl radical, a C.sub.4-C.sub.5
heterocycloalkyl radical, or a
--CH.sub.2--(C.sub.4-C.sub.6)heterocycloalkyl radical, R.sup.2
represents a hydrogen atom or a halogen atom, a linear or branched
C.sub.1-C.sub.5 alkyl radical, a linear or branched C.sub.2-C.sub.4
alkenyl radical, a C.sub.1-C.sub.4 alkoxy radical, a cyano group
--CN, a radical --C(.dbd.O)R'.sup.2 with R'.sup.2 denoting a
C.sub.1-C.sub.3 alkoxy radical, or a --CF.sub.3 radical; said
alkyl, alkenyl and alkoxy radicals optionally being substituted
with one or more halogen atoms, R.sup.3 represents a hydrogen atom,
a halogen atom, a group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7 or a
group CH.dbd.R.sup.7, n, o and p, which are identical or different,
represent zero or a natural integer ranging from 1 to 3, Z
represents a divalent group selected from the group consisting of a
methylene group --CH.sub.2--, an amino group --NH-- and an oxygen
atom --O--, R.sup.6 and R'.sup.6, which are identical or different,
represent a hydrogen atom, a methyl group --CH.sub.3, a group --OH,
a hydroxymethyl group, or a carboxylic function COOH, R.sup.7
represents: a hydrogen or a halogen atom, a group COOR'.sup.7 with
R'.sup.7 denoting (C.sub.1)alkyl(C.sub.6)heterocycle, a
heterocycloalkyl radical, wherein the heterocycloalkyl radical is
optionally substituted with one or more halogen atoms, one or more
linear or branched C.sub.1-C.sub.3 alkyl groups, one or more --OH
groups, one or more carbonyl functions, one or more linear or
branched C.sub.1-C.sub.4 hydroxyalkyl groups, one or more amino
groups, one or more groups --C(.dbd.O)R.sup.7a, or one or more
groups S(.dbd.O).sub.2R.sup.7a; R.sup.7a representing a linear or
branched C.sub.1-C.sub.3 alkyl radical, a linear or branched
C.sub.1-C.sub.3 alkoxy radical, or an amino radical
N(R.sup.8a)(R.sup.8b), a C.sub.3-C.sub.6 cycloalkyl radical,
wherein the cycloalkyl radical is optionally substituted with one
or more methyl radicals, one or more halogen atoms, a cyano group
--CN or one or more groups --COR.sup.13; R.sup.13 denoting a linear
or branched C.sub.1-C.sub.3 alkoxy radical, or a hydroxyl group, an
aromatic radical, wherein the aromatic radical is optionally
substituted with one or more halogen atoms, one or more linear or
branched C.sub.1-C.sub.3 alkyl groups optionally substituted with
one or more halogen atoms, one or more C.sub.1-C.sub.3 alkoxy
groups, one or more amino groups --NR.sup.11R.sup.12, one or more
groups --COR.sup.11, one or more groups --COOR.sup.11, one or more
amido groups CONR.sup.12, one or more groups --SOR.sup.11, one or
more groups --SO.sub.2R.sup.11, one or more groups --NHCOR.sup.11,
one or more groups --NHCOOR.sup.11, one or more groups
--SO.sub.2NR.sup.11R.sup.12 or one or more CN groups; R.sup.11 and
R.sup.12, which are identical or different, representing a hydrogen
atom, a hydroxyl radical --OH, or a linear or branched
C.sub.1-C.sub.3 alkyl radical optionally substituted with one or
more halogen atoms; or a heteroaromatic radical, wherein the
heteroaromatic radical is optionally substituted with one or more
halogen atoms, one or more linear or branched C.sub.1-C.sub.3 alkyl
groups optionally substituted with one or more halogen atoms, one
or more C.sub.1-C.sub.3 alkoxy groups, one or more amino groups
--NR.sup.11R.sup.12, one or more groups --COR.sup.11, one or more
groups --COOR.sup.11, one or more amido groups CONR.sup.11R.sup.12,
one or more groups --SOR.sup.11, one or more groups
--SO.sub.2R.sup.11, one or more groups --NHCOR.sup.11, one or more
groups --NHCOOR.sup.11, one or more groups
--SO.sub.2NR.sup.11R.sup.12 or one or more CN groups; R.sup.11 and
R.sup.12, which are identical or different, representing a hydrogen
atom, a hydroxyl radical --OH, a linear or branched C.sub.1-C.sub.3
alkyl radical optionally substituted with one or more halogen
atoms; R.sup.5 represents a hydrogen atom, a linear or branched
C.sub.1-C.sub.3 alkyl radical optionally substituted with one or
more halogen atoms; an amino radical --NH.sub.2, a C.sub.4-C.sub.5
heterocyclic radical, an OCH.sub.2--(C.sub.4-C.sub.5) heterocyclic
radical, a radical CH.sub.2R'.sup.7a with R'.sup.7a denoting a
methoxy radical, a hydroxyl group --OH, a --CH.sub.2COOH group, a
group --CH(R.sup.5b)OH, a carboxylic group --COOH, a --CN group, or
a thioxo function, R.sup.5b represents a hydrogen atom, a linear or
branched C.sub.1-C.sub.3 alkyl radical optionally substituted with
one or more carboxylic functions, or a cyclopropyl radical, and
R.sup.8a and R.sup.8b, which are identical or different, denote a
hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical
or a cyclopropyl radical.
3. The compound of formula (II) as defined by claim 1, wherein the
compound is selected from the group consisting of: TABLE-US-00008
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4
ethylphenyl)(1 ethylpropyl)amide Compound 1, ##STR00298##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
((R)-sec- butyl)(4-ethylphenyl)amide Compound 2, ##STR00299##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
cyclopropyl(4-ethylphenyl)amide Compound 3, ##STR00300##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
ethylphenyl)(tetrahydropyran-4- ylmethyl)amide Compound 5,
##STR00301## 1-((3,5-dimethylisoxazol-4-
yl)methyl)-N-(4-ethylphenyl)-N- isobutyl-1H-indazole-5-sulfonamide
Compound 6, ##STR00302## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid butyl(4- isopropylphenyl)amide Compound 7,
##STR00303## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (4- ethylphenyl)propyl Compound 8, ##STR00304##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
butyl(4- ethylphenyl)amide Compound 9, ##STR00305##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(5-chloro-2- fluorophenyl)isobutylamide Compound 10, ##STR00306##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,5-
dimethylphenyl)isobutylamide Compound 11, ##STR00307##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-
methoxypyridin-2-yl)isobutylamide Compound 12, ##STR00308##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(4-butyl-2- methylphenyl)isobutylamide Compound 13, ##STR00309##
N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydro-2H-pyran-4-yl)methyl)-
1H-indazole-5-sulfonamide Compound 14, ##STR00310##
3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide
Compound 15, ##STR00311## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid (4- ethylphenyl)oxetan-3-ylmethylamide
Compound 16, ##STR00312## 1-(1-acetylpyrrolidin-3-yl)-1H-
indazole-5-sulfonic acid (4- ethylphenyl)isobutylamide Compound 17,
##STR00313## 3-(tetrahydropyran-4-ylmethoxy)-1-
(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
ehtlyphenyl)isobutylamide Compound 18, ##STR00314##
1-(3,5-dimethylisoxazol-4-ylmethyl)- 1H-indazole-5-sulfonic acid
(4- ethylphenyl)isobutylamide Compound 19, ##STR00315##
1-((1-acetylpyrrolidin-3-yl)methyl)-N-
(4-ethylphenyl)-N-isobutyl-1H- indazole-5-sulfonamide Compound 20,
##STR00316## N-(4-ethylphenyl)-N-isobutyl-1-
((tetrahydrofuran-3-yl)methyl)-1H- indazole-5-sulfonamide Compound
21, ##STR00317## N-(4-ethylphenyl)-N-isobutyl-1-
((tetrahydro-2H-pyran-3-yl)methyl)- 1H-indazole-5-sulfonamide
Compound 22, ##STR00318## 1-benzyl-N-(4-ethylphenyl)-N-
isobutyl-1H-indazole-5-sulfonamide Compound 23, ##STR00319##
N-(cyclobutylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran-
4-yl)methyl)-1H-indazole-5- sulfonamide Compound 24, ##STR00320##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-
methoxyphenyl)isobutylamide Compound 25, ##STR00321##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-
methylphenyl)isobutylamide Compound 26, ##STR00322##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,4-
dimethylphenyl)isobutylamide Compound 27, ##STR00323##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3,5-
dimethylphenyl)isobutylamide Compound 28, ##STR00324##
N-(4-ethylphenyl)-N-isopropyl-1-
((tetrahydro-2H-pyran-4-yl)methyl)- 1H-indazole-5-sulfonamide
Compound 29, ##STR00325## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid sec-butyl(4- ethylphenyl)amide Compound
30, ##STR00326## N-(cyclopropylmethyl)-N-(4-
ethylphenyl)-1-((tetrahydro-2H-pyran- 4-yl)methyl)-1H-indazole-5-
sulfonamide Compound 31, ##STR00327##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
cyclopentyl(4-ethylphenyl)amide Compound 32, ##STR00328##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
ethylphenyl)(tetrahydrofuran-3- ylmethyl)amide Compound 33,
##STR00329## 3-amino-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide Compound 34, ##STR00330##
N-(4-ethylphenyl)-N-isopentyl-1-
((tetrahydro-2H-pyran-4-yl)methyl)- 1H-indazole-5-sulfonamide
Compound 35, ##STR00331## N-(4-ethylphenyl)-N-isobutyl-1-
(pyridin-4-ylmethyl)-1H-indazole-5- sulfonamide Compound 36,
##STR00332## N-(4-ethylphenyl)-N-isopentyl-1-
(oxetan-3-ylmethyl)-1H-indazole-5- sulfonamide Compound 37
##STR00333## 1-(tetrahydropyran-4-yl)-1H-indazole- 5-sulfonic acid
(4- ethylphenyl)isobutylamide Compound 38, ##STR00334##
N-(4-ethylphenyl)-N-isopentyl-1-
((tetrahydro-2H-pyran-4-yl)methyl)- 1H-indazole-5-sulfonamide
Compound 39, ##STR00335## 1-(1-acetylpyrrolidin-3-yl)-1H-
indazole-5-sulfonic acid (4- ethylphenyl)isobutylamide Compound 40,
##STR00336## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid cyclobutyl(4- ethylphenyl)amide Compound 41, ##STR00337##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(5-fluoro-2- methylphenyl)isobutylamide Compound 42, ##STR00338##
1-(tetrahydropyran-4-ylmethyl)-2H- indazole-5-sulfonic acid
(3-fluoro-2- methylphenyl)isobutylamide Compound 43, ##STR00339##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-
chlorophenyl)isobutylamide Compound 44, ##STR00340##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2-
chlorophenyl)isobutylamide Compound 45, ##STR00341##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
fluorophenyl)isobutylamide Compound 46, ##STR00342##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl-p- tolylamide Compound 47, ##STR00343##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl-o- tolylamide Compound 48, ##STR00344##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
trifluoromethoxyphenyl) isobutylamide Compound 49, ##STR00345##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl(5- isopropylpyridin-2-yl)amide Compound 50, ##STR00346##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(3-chloro- benzyl)isobutylamide Compound 51, ##STR00347##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl(2- trifluoromethylbenzyl)amide Compound 52, ##STR00348##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(2-fluoro-6- methylphenyl)isobutylamide Compound 53, ##STR00349##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(4-fluoro-2- methylphenyl)isobutylamide Compound 54, ##STR00350##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl(4- methoxy-2-methylphenyl)amide Compound 55, ##STR00351##
methyl 4-{isobutyl[1- (tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonyl]amino}-3- methylbenzoate Compound 56,
##STR00352## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (4-cyano-2- methylphenyl)isobutylamide Compound 57,
##STR00353## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid isobutyl(2- trifluoromethylphenyl)amide Compound 58,
##STR00354## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid isobutyl(4- trifluoromethylphenyl)amide Compound 59,
##STR00355## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (3-chloro-2- hydroxymethylpropyl)(4- ethylphenyl)amide
Compound 60, ##STR00356## 3-(tetrahydropyran-4-ylmethoxy)-1H-
indazole-5-sulfonic acid (4- ethylphenyl)isobutylamide Compound 61,
##STR00357## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid isobutyl-o- tolylamide Compound 69, ##STR00358##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(2-cyano-4- methylphenyl)isobutylamide Compound 70, ##STR00359##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4,6-
dimethylpyridin-3-yl)isobutylamide Compound 71, and ##STR00360##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(2-fluoro-4- methylphenyl)isobutylamide Compound 73.
4. A pharmaceutical composition comprising at least one compound of
formula (II) according to claim 1, or a pharmaceutically acceptable
salt thereof, a hydrate thereof, or a solvate thereof.
5. The pharmaceutical composition as defined by claim 4, wherein
the composition is formulated for topical or oral
administration.
6. The pharmaceutical composition as defined by claim 4, wherein
the composition is formulated for treating acne, atopic dermatitis
and/or psoriasis.
7. The pharmaceutical composition as defined by claim 5, wherein
the composition is formulated for oral administration in the form
of a table, a gel capsule, a coated tablet, a syrup, a suspension,
a solution, a powder, a granule, an emulsion, a suspension
comprising a microsphere, a suspension comprising a nanosphere, a
lipid vesical, or a polymeric vesicle.
8. The pharmaceutical composition as defined by claim 5, wherein
the composition is formulated for topical administration in the
form of an ointment, a cream, a milk, a pomade, a powder, an
impregnated pad, a syndet, a solution, a gel, a spray, a mousse, a
suspension, a stick, a shampoo, or a washing base.
9. The compound of formula (II) as defined by claim 1, wherein
R.sup.7 represents a heterocyclic radical selected from the group
consisting of: ##STR00361## in which: R.sup.7a represents a linear
or branched C.sub.1-C.sub.3 alkyl radical, and R.sup.8 and R.sup.9
represent a hydrogen atom.
10. The compound of formula (II) as defined by claim 1, wherein
R.sup.7 represents an aromatic or heteroaromatic radical selected
from the group consisting of: ##STR00362## in which: R.sub.10
represents a hydrogen atom or a linear or branched C.sub.1-C.sub.3
alkyl group, and m denotes zero or a natural integer ranging from 1
to 3.
11. The compound of formula (III) as defined by claim 2, wherein
R.sup.7 represents a heterocyclic radical selected from the group
consisting of: ##STR00363## in which: R.sup.7a represents a linear
or branched C.sub.1-C.sub.3 alkyl radical, a linear or branched
C.sub.1-C.sub.3 alkoxy radical or an amino radical
N(R.sup.8a)(R.sup.8b), R.sup.8a and R.sup.8b, which may be
identical or different, denote a hydrogen atom, a linear or
branched C.sub.1-C.sub.3 alkyl radical or a cyclopropyl radical,
R.sub.8 and R.sub.9, which are identical or different, represent a
hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical,
a hydroxyl group --OH, a carbonyl function .dbd.O, a C.sub.1
hydroxyalkyl radical (--CH.sub.2OH), or an amino group NH.sub.2,
and R.sub.8 and R.sub.9 can form, together with the carbon atoms to
which they are attached, a 5- to 7-membered carbocyclic ring.
12. The compound of formula (III) as defined by claim 2, wherein
R.sup.7 represents an aromatic or heteroaromatic radical selected
from the group consisting of: ##STR00364## in which: R.sub.10
represents a hydrogen atom or a halogen atom, one linear or
branched C.sub.1-C.sub.3 alkyl group optionally substituted with
one or more halogen atoms, one C.sub.1-C.sub.3 alkoxy group, one
amino group --NR.sup.11R.sup.12, one group --COR.sup.11, one group
--COOR.sup.11, one amido group --CONR.sup.11R.sup.12, one group
--SOR.sup.11, one group --SO.sub.2R.sup.11, one group
--NHCOR.sup.11, one group --NHCOOR.sup.11, one group
--SO.sub.2NR.sup.11R.sup.12 or one --CN group; R.sup.11 and
R.sup.12, which are identical or different, representing a hydrogen
atom or a linear or branched C.sub.1-C.sub.3 alkyl radical
optionally substituted with one or more halogen atoms, and m
denotes zero or a natural integer ranging from 1 to 3.
13. The compound of formula (III) as defined by claim 2, wherein
the compound is selected from the group consisting of:
TABLE-US-00009 ##STR00365## 3-bromo-1-(tetrahydropyran-2-yl)-1H-
indazole-6-sulfonic acid (4- ethylphenyl)isobutylamide Compound 4,
##STR00366## 3-(tetrahydropyran-4-ylidenemethyl)-
1H-indazole-6-sulfonic acid (4- ethylphenyl)isobutylamide Compound
62, ##STR00367## 3-(tetrahydropyran-4-ylmethyl)-1H-
indazole-6-sulfonic acid (4- ethylphenyl)isobutylamide Compound 63,
##STR00368## 3-morpholin-4-ylmethyl-1H-indazole- 6-sulfonic acid
(4- ethylphenyl)isobutylamide Compound 64, ##STR00369##
3-((cis)-2,6-dimethylmorpholin-4- ylmethyl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide Compound 65, and ##STR00370##
3-((S)-3-methylmorpholin-4- ylmethyl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide Compound 66.
14. A pharmaceutical composition comprising at least one compound
of formula (III) according to claim 2, or a pharmaceutically
acceptable salt thereof, a hydrate thereof, or a solvate
thereof.
15. The pharmaceutical composition as defined by claim 14, wherein
the composition is formulated for topical or oral
administration.
16. The pharmaceutical composition as defined by claim 14, wherein
the composition is formulated for treating acne, atopic dermatitis
and/or psoriasis.
17. The pharmaceutical composition as defined by claim 15, wherein
the composition is formulated for oral administration in the form
of a table, a gel capsule, a coated tablet, a syrup, a suspension,
a solution, a powder, a granule, an emulsion, a suspension
comprising a microsphere, a suspension comprising a nanosphere, a
lipid vesical, or a polymeric vesicle.
18. The pharmaceutical composition as defined by claim 15, wherein
the composition is formulated for topical administration in the
form of an ointment, a cream, a milk, a pomade, a powder, an
impregnated pad, a syndet, a solution, a gel, a spray, a mousse, a
suspension, a stick, a shampoo, or a washing base.
19. A compound selected from the group consisting of: ##STR00371##
##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376##
##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381##
##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386##
##STR00387##
Description
The present invention relates to particular bicyclic sulfonamide
derivatives, to the pharmaceutically acceptable addition salts
thereof, hydrates thereof and/or solvates thereof, and also to the
use thereof as inverse agonist of the retinoid-related orphan
receptor gamma ROR.gamma.t.
The invention also relates to a pharmaceutical composition
comprising such compounds and also to the use thereof for the
topical and/or oral treatment of inflammatory diseases mediated by
the ROR.gamma.t receptors, especially acne, atopic dermatitis
and/or psoriasis.
The nuclear receptors form a large family (known as a superfamily)
of transcription factors which correspond to proteins that are
capable of being activated by a ligand, of binding to specific DNA
sequences and of regulating the transcription of target genes.
Thus, these receptors are involved in the regulation of a wide
variety of biological functions, including growth, development,
reproduction, differentiation and metabolism in a multitude of
living organisms.
The first members of this superfamily that were identified and
described in the scientific literature are the nuclear receptors of
steroid hormones such as the glucocorticoid receptors and the
estrogen receptors. This superfamily also comprises among its
members many receptors for which no ligand has been identified.
These nuclear receptors are known as "orphan receptors".
Retinoid-related orphan receptors thus constitute a subfamily of
nuclear receptors. This subfamily is composed of three members each
having an intrinsic expression profile: ROR alpha (known as
ROR.alpha.), ROR beta (known as ROM and ROR gamma (known as
ROR.gamma.). Two isoforms of the orphan receptors ROR.gamma. have
already been identified, namely ROR.gamma.1, which is expressed in
a variety of tissues such as the thymus, the kidneys, muscles and
the liver, and ROR.gamma.2 (also known as ROR.gamma.t), which is
expressed exclusively in the cells of the immune system.
In particular, the receptor ROR.gamma.t plays an important
regulating role in cell differentiation of the Th17 lymphocytes
which correspond to helper T lymphocytes whose function is to
ensure the defence of the body against a large number of
extracellular pathogens such as bacteria and fungal infections.
However, it has been demonstrated that the Th17 lymphocytes are
also involved in a wide variety of inflammatory disorders, such as
acne, and of autoimmune diseases such as psoriasis, rheumatoid
arthritis or multiple sclerosis (Peck A, Mellins E D. Precarious
balance; Th17 cells in host defense. Infect. Immun. 2010 January;
78(1): 32-8; Suarez-Farinas: J. Allergy Clin. Immunol. 2014; J.
Invest. Dermatol. 2008, 128(11), 2625).
Specifically, the Th17 lymphocytes produce numerous cytokines which
have distinct profiles, such as interleukin-17A (IL-17A),
interleukin-17F (IL-17F), interleukin-26 (IL-26), interleukin-21
(IL-21), interleukin-22 (IL-22) and TNF.alpha., the development,
survival and proliferation of which depend on interleukin-23
(IL-23). These cytokines are capable of activating different types
of effector cells, such as keratinocytes, thus leading to their
hyperproliferation and to the additional production of
pro-inflammatory cytokines, chemokines and antimicrobial peptides,
which in turn recruit and activate other immune system cells in the
inflamed skin, which may lead to amplification of the immune
response.
Thus, activation of the Th17 lymphocytes is responsible for the
recruitment of cytokines, especially of interleukin-17 (IL17), and
of other types of pro-inflammatory cells, which will lead to the
mediation of inflammatory disorders such as acne and/or of
autoimmune diseases such as psoriasis.
Experiments conducted on mice show that a decrease in the level of
expression of the ROR.gamma.t receptor leads to a decrease in the
activity of the Th17 lymphocytes, which consequently makes it
possible to greatly reduce the expression of interleukin-17 (IL-17)
(Ivanov I I, McKenzie B S, Zhou L, Tadokoro C E, Lepelley A,
Lafaille J J, Cua D J, Littman D R: Cell 2006, 126, 1121-1133) and
to efficiently treat inflammatory disorders and autoimmune diseases
mediated by these cytokines, especially those for which high levels
of interleukin-17 (IL-17) are detected.
To this end, patent application WO 2013/160 418 describes
sulfonamide compounds used as inverse agonists of the ROR.gamma.t
receptor in order to be able to treat inflammatory disorders and
autoimmune diseases. Similarly, other compounds have also been
developed as inverse agonists of the ROR.gamma.t receptor, such as
those described in patent applications WO 2014/090 712, WO 2014/008
214, WO 2013/169 588, WO 2013/160 419, WO 2013/1 002 027, WO
2013/092 939, WO 2013/092 941, WO 2013/085 890 and WO 2012/100
732.
There is thus a real need to develop novel compounds as inverse
agonists of the ROR.gamma.t receptor in order to be able to
efficiently treat diseases mediated by such a receptor, especially
inflammatory disorders such as acne, and/or autoimmune diseases
such as psoriasis or atopic dermatitis.
This aim is achieved by means of the use of particular bicyclic
sulfonamide derivatives as described below, which make it possible
to modulate the activity of the ROR.gamma.t receptor and
consequently to efficiently treat inflammatory disorders and
autoimmune diseases of certain pathologies.
One subject of the present invention is thus especially one or more
compounds of formula (Ia), the pharmaceutically acceptable addition
salts thereof, hydrates thereof and/or solvates thereof:
##STR00001##
in which formula (I): L represents a single bond or a methylene
group CH.sub.2, X represents a cyclic radical chosen from the
radicals X.sub.1 and X.sub.2 below:
##STR00002## one or two of the elements Y.sup.1, Y.sup.2, Y.sup.3,
Y.sup.4 and Y.sup.5 represent(s) a nitrogen atom and the other
elements correspond to a group --CR.sup.2, or each of the elements
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 corresponds to a
group --CR.sup.2, one or two of the elements Q.sup.1, Q.sup.2 and
Q.sup.3 represent(s) a nitrogen atom and the other element(s)
correspond(s) to a group --CR.sup.2a, or each of the elements
Q.sup.1, Q.sup.2 and Q.sup.3 corresponds to a group --CR.sup.2a,
R.sup.1 represents a linear or branched C.sub.3-C.sub.5 alkyl
radical, optionally substituted with a hydroxyl group and/or a
halogen atom, a C.sub.3-C.sub.5 cycloalkyl radical, a linear or
branched C.sub.2-C.sub.5 alkenyl radical, a
(C.sub.1)alkyl(C.sub.3-C.sub.5)cycloalkyl radical, a
C.sub.4-C.sub.5 heterocycloalkyl radical, a
(C.sub.1)alkyl(C.sub.4-C.sub.6)heterocycloalkyl radical, R.sup.2
represents a hydrogen atom or a halogen atom, a linear or branched
C.sub.1-C.sub.5 alkyl radical, a linear or branched C.sub.2-C.sub.4
alkenyl radical, a C.sub.1-C.sub.4 alkoxy radical, a cyano group
--CN, a radical --C(.dbd.O)R'.sup.2 with R'.sup.2 denoting a
C.sub.1-C.sub.3 alkoxy radical, a --CF.sub.3 radical; said alkyl,
alkenyl and alkoxy radicals possibly being substituted with one or
more halogen atoms, R.sup.2a represents a hydrogen atom or a
halogen atom, a linear or branched C.sub.1-C.sub.5 alkyl radical, a
linear or branched C.sub.2-C.sub.4 alkenyl radical, a
C.sub.1-C.sub.4 alkoxy radical, a --CN group, a hydroxyl group
--OH, a group --CH(R.sup.3a)OH, a carboxylic group --COOH, a
carbamoyl group --CONR.sup.2cR.sup.2d, an amido group
--NR.sup.2cCOR.sup.2d, a group --SO.sub.2R.sup.2c, a group
--SOR.sup.2c, a group --S(.dbd.O)(.dbd.NH--R.sup.2c), said alkyl,
alkenyl and alkoxy radicals possibly being substituted with one or
more halogen atoms, R.sup.2c and R.sup.2d, which may be identical
or different, represent a hydrogen atom or a linear or branched
C.sub.1-C.sub.5 alkyl radical; R.sup.3a represents a hydrogen atom
or a linear or branched C.sub.1-C.sub.5 alkyl radical, R.sup.3
represents a hydrogen atom, a halogen atom, a group
(CHR.sup.6).sub.n--(Z)O--(CHR '.sup.6).sub.p--R.sup.7, a group
CH.dbd.R.sup.7 or a group --C.dbd.CH--R.sup.7, n, o and p, which
may be identical or different, represent zero or a natural integer
ranging from 1 to 3, --Z represents a divalent group chosen from a
methylene group --CH.sub.2--, an amino group --NH-- and an oxygen
atom --O--, R.sup.6 and R'.sup.6, which may be identical or
different, represent a hydrogen atom, a methyl group --CH.sub.3, a
group --OH, a C.sub.1 hydroxyalkyl group, a carboxylic function
--COOH, R.sup.7 represents: a hydrogen atom or a halogen atom, a
group COOR'.sup.7 with R'.sup.7 denoting
(C.sub.1)alkyl(C.sub.6)heterocycle, a non-cationic heterocyclic
radical optionally substituted with one or more halogen atoms, one
or more linear or branched C.sub.1-C.sub.3 alkyl groups, one or
more --OH groups, one or more carbonyl functions, one or more
linear or branched C.sub.1-C.sub.4 hydroxyalkyl groups, one or more
amino groups, one or more groups --C(.dbd.O)R.sup.7a, one or more
groups S(.dbd.O).sub.2R.sup.7a; R.sup.7a representing a linear or
branched C.sub.1-C.sub.3 alkyl radical, a linear or branched
C.sub.1-C.sub.3 alkoxy radical, or an amino radical
N(R.sup.8a)(R.sup.8b), a non-cationic C.sub.3-C.sub.6 cycloalkyl
radical optionally substituted with one or more C.sub.1 alkyl
radicals, one or more halogen atoms, a cyano group --CN or one or
more groups --COR.sup.9; R.sup.9 denoting a linear or branched
C.sub.1-C.sub.3 alkoxy radical, or a hydroxyl group, an aromatic or
heteroaromatic, non-cationic radical optionally substituted with
one or more halogen atoms, one or more linear or branched
C.sub.1-C.sub.3 alkyl groups optionally substituted with one or
more halogen atoms, one or more C.sub.1-C.sub.3 alkoxy groups, one
or more amino groups --NR.sup.11R.sup.12, one or more groups
--COR.sup.11, one or more groups --COOR.sup.11, one or more amido
groups --CONR.sup.11R.sup.12, one or more groups --SOR.sup.11, one
or more groups --SO.sub.2R.sup.11, one or more groups
--NHCOR.sup.11, one or more groups --NHCOOR.sup.11, one or more
groups --SO.sub.2NR.sup.11R.sup.12 or one or more --CN groups;
R.sup.11 and R.sup.12, which may be identical or different,
representing a hydrogen atom, a hydroxyl radical --OH, a linear or
branched C.sub.1-C.sub.3 alkyl radical optionally substituted with
one or more halogen atoms; when R.sup.3 represents a group
--CH.dbd.R.sup.7 or a group --C.dbd.CH--R.sup.7, then R.sup.7 does
not represent a hydrogen atom, a halogen atom or a group
COOR'.sup.7, R.sup.5 represents a hydrogen atom or a halogen atom,
a linear or branched C.sub.1-C.sub.3 alkyl radical optionally
substituted with one or more halogen atoms; an amino radical
--NH.sub.2, a C.sub.4-C.sub.5 heterocyclic radical, an
OCH.sub.2--(C.sub.4-C.sub.5)heterocyclic radical, a radical
CH.sub.2R.sup.'7a with R'.sup.7a denoting a C.sub.1 alkoxy radical,
a hydroxyl group-OH, a --CH.sub.2COOH group, a group
--CH(R.sup.5b)OH, an amino group --NH.sub.2, a carboxylic group
--COOH, a --CN group, a thioxo function, R.sup.5b represents a
hydrogen atom, a linear or branched C.sub.1-C.sub.3 alkyl radical
optionally substituted with one or more carboxylic functions; a
cyclopropyl radical, R.sup.8a and R.sup.8b, which may be identical
or different, denote a hydrogen atom, a linear or branched
C.sub.1-C.sub.3 alkyl radical or a cyclopropyl radical.
The compound(s) according to the invention thus correspond to
bicyclic sulfonamide derivatives, and thus to one or more
sulfonamide compounds bearing in their structure at least two rings
that are fused to each other.
In other words, X is a cyclic radical fused to the aromatic
nucleus, comprising the elements Q.sup.1, Q.sup.2 and Q.sup.3 as
defined above.
In accordance with the definition of formula (I), the endocyclic
bond between the cyclic radical X.sub.1 or X.sub.2, as represented
above, and the aromatic nucleus comprising the elements Q.sub.1 to
Q.sub.3 is a double bond. Thus, the double bond is common between
the cyclic radical X.sub.1 or X.sub.2 and the aromatic nucleus
comprising the elements Q.sub.1 to Q.sub.3.
The compounds according to the invention make it possible to
modulate, i.e. to inhibit, the activity of the ROR.gamma.t
receptor.
A subject of the present invention is also the compound(s) as
defined previously, as medicament and cosmetic.
Another subject of the invention relates to the compound(s) as
defined previously for their use in the treatment of diseases
mediated by the ROR.gamma.t receptor, especially inflammatory
disorders and/or autoimmune diseases mediated by the ROR.gamma.t
receptor.
Moreover, the invention also relates to a pharmaceutical
composition comprising, in a pharmaceutically acceptable medium,
one or more compounds of formula (I) as defined previously,
pharmaceutically acceptable addition salts thereof, hydrates
thereof and/or solvates thereof.
The present invention also relates to the pharmaceutical
composition as described previously, for its use in the treatment
of diseases mediated by the ROR.gamma.t receptor, especially
inflammatory disorders and/or autoimmune diseases.
Finally, the invention relates to a method for treating diseases
mediated by the ROR.gamma.t receptor, comprising the
administration, especially topically or orally, of a
therapeutically effective amount of one or more compounds as
defined above to a patient.
Other subjects, characteristics, aspects and advantages of the
invention will emerge even more clearly on reading the description
and the examples that follow.
According to one embodiment, in formula (I): R.sup.3 represents a
hydrogen atom, a group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR.sup.16).sub.p--R.sup.7, a group
CH.dbd.R.sup.7 or a group --C.dbd.CH--R.sup.7, and R.sup.5
represents a hydrogen atom or a halogen atom, a linear or branched
C.sub.1-C.sub.3 alkyl radical optionally substituted with one or
more halogen atoms; an amino radical --NH.sub.2, a radical
CH.sub.2R'.sup.7a with R'.sup.7a denoting a C.sub.1 alkoxy radical,
a hydroxyl group --OH, a --CH.sub.2COOH group, a group
--CH(R.sup.5b)OH, an amino group --NH.sub.2, a carboxylic group
--COOH, a --CN group, a thioxo function.
According to one embodiment, in formula (I), L represents a single
bond.
According to another embodiment, in formula (I), L represents a
methylene group --CH.sub.2.
Preferentially, in formula (I), L represents a single bond.
Preferably: when R.sup.5 is linked to the nitrogen atom, then
R.sup.5 represents a hydrogen atom or a --CH.sub.2COOH group, when
R.sup.5 is linked to a carbon atom belonging to the cyclic radical
X, then R.sup.5 represents a hydroxyl group --OH, a group
--CH(R.sup.5b)OH, an amino group --NH.sub.2, a carboxylic group
--COOH, a halogen atom or a --CN group.
Preferentially, when X.dbd.X.sub.1, then R.sup.3 is other than a
halogen atom and when X.dbd.X.sub.2, then R.sup.5 represents a
hydrogen atom or a linear or branched C.sub.1-C.sub.3 alkyl radical
optionally substituted with one or more halogen atoms.
More preferentially, R.sup.3 and R.sup.5 are different.
Even more preferentially, R.sup.3 represents a hydrogen atom or a
group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7.
According to one embodiment, R.sup.3 represents a hydrogen atom or
a group (CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7
and R.sup.5 represents a hydrogen atom or a linear or branched
C.sub.1-C.sub.3 alkyl radical, optionally substituted with one or
more halogen atoms.
Preferably, R.sup.11 and R.sup.12 are other than an --OH group.
According to one embodiment, in formula (I), R.sup.3 represents a
hydrogen atom.
According to one embodiment, in formula (I), R.sup.3 represents a
group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7.
According to one embodiment, in formula (I), the indices n, o and
p, which may be identical or different, denote zero.
According to one embodiment, in formula (I), the indices n, o and
p, which may be identical or different, denote a natural integer
ranging from 1 to 3.
According to one embodiment, in formula (I), the indices n and p
denote zero and the index o is equal to 1.
According to one embodiment, in formula (I), Z represents a
methylene group --CH.sub.2.
According to one embodiment, in formula (I), Z represents a
divalent group-O--.
According to one embodiment, in formula (I), Z represents a
divalent group-NH--.
According to one embodiment, in formula (I), R.sup.3 represents a
group Z--R.sup.7, with Z having the meaning described
previously.
According to a particular embodiment, in formula (I), R.sup.3
represents a group-CH.sub.2--R.sup.7.
According to a particular embodiment, in formula (I), R.sup.3
represents a group-O--R.sup.7.
According to a particular embodiment, in formula (I), R.sup.3
represents a group-NH--R.sup.7.
According to one embodiment, in formula (I), R.sup.7 represents a
heterocyclic radical chosen from the following heterocycles:
##STR00003## ##STR00004##
in which: R.sub.7a represents a linear or branched C.sub.1-C.sub.3
alkyl radical, a linear or branched C.sub.1-C.sub.3 alkoxy radical
or an amino radical N(R.sup.8a)(R.sup.8b), R.sup.8a and R.sup.8b,
which may be identical or different, denote a hydrogen atom, a
linear or branched C.sub.1-C.sub.3 alkyl radical or a cyclopropyl
radical, R.sub.8 and R.sub.9, which may be identical or different,
represent a hydrogen atom, a linear or branched C.sub.1-C.sub.3
alkyl radical, a hydroxyl group --OH, a carbonyl function .dbd.O, a
C.sub.1 hydroxyalkyl radical (--CH.sub.2OH), an amino group
NH.sub.2, R.sub.8 and R.sub.9 can form, together with the carbon
atoms to which they are attached, a 5- to 7-membered carbocyclic
ring.
According to one embodiment, in formula (I), R.sup.7 represents an
aromatic or heteroaromatic radical chosen from:
##STR00005##
in which: R.sub.10 represents a hydrogen atom or a halogen atom,
one linear or branched C.sub.1-C.sub.3 alkyl group optionally
substituted with one or more halogen atoms, one C.sub.1-C.sub.3
alkoxy group, one amino group --NR.sup.11R.sup.12, one group
--COR.sup.11, one group --COOR.sup.11, one amido group
--CONR.sup.11R.sup.12, one group --SOR.sup.11, one group
--SO.sub.2R.sup.11, one group --NHCOR.sup.11, one group
--NHCOOR.sup.11, one group --SO.sub.2R.sup.11R.sup.12 or one --CN
group; R.sup.11 and R.sup.12, which may be identical or different,
representing a hydrogen atom or a linear or branched
C.sub.1-C.sub.3 alkyl radical optionally substituted with one or
more halogen atoms, m denotes zero or a natural integer ranging
from 1 to 3.
Preferably, R.sup.11 and R.sup.12 are other than an --OH group.
Preferentially, R.sup.7 represents an aromatic or heteroaromatic
radical as defined previously, optionally substituted with one or
more methyl groups --CH.sub.3, one or more methoxy groups
--OCH.sub.3, one or more hydroxyl groups --OH, one or more amino
groups --NH.sub.2, one or more --CH.sub.2OH groups, one or more
cyano groups --CN, one or more halogen atoms or one or more
carbonyl functions.
According to one embodiment, the index m is equal to zero.
According to one embodiment, the index m denotes a natural integer
ranging from 1 to 3.
Preferentially, the index m is equal to 1.
According to one embodiment, in formula (I), each of the elements
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 corresponds to a
group --CR.sup.2 with R.sup.2 having the same meaning as that
described previously.
According to one embodiment, in formula (I), each of the elements
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 corresponds to a
group --CR.sup.2 with R.sup.2 representing a hydrogen atom.
According to one embodiment, in formula (I), each of the elements
Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 corresponds to a
group --CR.sup.2 with R.sup.2 representing a linear or branched
C.sub.1-C.sub.5 alkyl radical.
According to one embodiment, in formula (I), each of the elements
Q.sup.1, Q.sup.2 and Q.sup.3 represents a group --CR.sup.2a with
R.sup.2a having the same meaning as that described previously.
According to one embodiment, in formula (I), each of the elements
Q.sup.1, Q.sup.2 and Q.sup.3 represents a group --CR.sup.2a with
R.sup.2a representing a hydrogen atom.
According to one embodiment, in formula (I), Q.sup.1 and Q.sup.2
represent a group --CR.sup.2a with R.sup.2a representing a hydrogen
atom and Q.sup.3 represents a group --CR.sup.2a with R.sup.2a
representing a linear or branched C.sub.1-C.sub.5 alkyl
radical.
According to one embodiment, in formula (I), IV represents a linear
or branched C.sub.3-C.sub.5 alkyl radical, preferably a branched
C.sub.3-C.sub.5 and more preferentially branched C.sub.4 alkyl
radical.
According to one embodiment, in formula (I), IV represents a
C.sub.3-C.sub.5 cycloalkyl radical, preferably cyclopropyl.
According to one embodiment, in formula (I), R.sup.1 represents a
linear or branched C.sub.2-C.sub.5 alkenyl radical.
According to one embodiment, in formula (I), R.sup.1 represents a
CH.sub.2--(C.sub.3-C.sub.5)cycloalkyl radical.
According to one embodiment, in formula (I), R.sup.1 represents a
C.sub.4-C.sub.5 heterocycloalkyl radical.
According to one embodiment, in formula (I), R.sup.1 represents a
CH.sub.2--(C.sub.4-C.sub.6)heterocycloalkyl radical, in particular
a CH.sub.2--(C.sub.4-C.sub.5)heterocycloalkyl radical.
Preferentially, R.sup.1 represents a linear or branched
C.sub.3-C.sub.5 alkyl radical, or a
CH.sub.2--(C.sub.4-C.sub.5)heterocycloalkyl radical.
According to one embodiment, R.sup.5 represents a hydrogen
atom.
Preferably, the compound(s) of formula (I) are chosen from the
compound(s) of formula (II), the pharmaceutically acceptable
addition salts thereof, hydrates thereof and/or solvates
thereof:
##STR00006##
in which formula (II) R.sup.1, R.sup.3, R.sup.5 and Y.sup.1 to
Y.sup.5 have the same meanings as in formula (I) described
previously.
Preferentially, R.sup.3 represents a group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7 with
R.sup.6, Z, R'.sup.6, R.sup.7 and the indices n, o and p having the
same meanings as those indicated previously.
More preferentially, R.sup.3 represents a group CH.sub.2--R.sup.7
with R.sup.7 representing a non-cationic heterocyclic radical.
Preferably, the compound(s) of formula (I) are chosen from the
compound(s) of formula (III), the pharmaceutically acceptable
addition salts thereof, hydrates thereof and/or solvates
thereof:
##STR00007##
in which formula (III) R.sup.1, R.sup.3, R.sup.5 and Y.sup.1 to
Y.sup.5 have the same meanings as in formula (I) described
previously.
Preferentially, in formula (III), R.sub.5 represents a hydrogen
atom or a linear or branched C.sub.1-C.sub.3 alkyl radical
optionally substituted with one or more halogen atoms.
The compounds of formula (I) may be in the form of pharmaceutically
acceptable salts. Examples of pharmaceutically acceptable salts are
described in Berge et al., 1977, "Sels pharmaceutiquement
acceptables" [Pharmaceutically acceptable salts], J. Pharm. Sci.,
Vol. 66, pages 1-19.
In particular, when the compounds of formula (I) according to the
invention are in the form of salts, then the electrical neutrality
of said compounds is ensured by an external cationic counterion Y
which may be organic or mineral.
Y may be chosen from suitable inorganic cations such as alkali
metal ions, especially Na.sup.+, K.sup.+, alkaline-earth metal
ions, especially Ca.sup.2+, Mg.sup.2+, or alternatively other
cations such as the aluminum ion Al.sup.3+.
Y may be chosen from suitable organic cations such as the ammonium
ion NH.sub.4+, substituted ammonium ions such as NH.sub.3R.sup.+,
NHR.sub.2.sup.+, NR.sub.4.sup.+ with R representing a
C.sub.1-C.sub.4 alkyl radical.
In particular, the substituted ammonium ions are those chosen from
derivatives of ethylamine, diethylamine, dicyclohexylamine,
triethylamine, butylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine, benzylamine, phenylbenzylamine,
choline, meglumine and tromethamine, and amino acids such as lysine
and arginine.
An example of a quaternary ammonium ion may be the ion N.sup.+
(CH.sub.3).sub.4.
The compound(s) according to the invention may be in the form of
the solvates thereof.
For the purposes of the present invention, the term "solvate" means
a complex of solute (i.e. the compound according to the invention
or the salt of said compound) and of solvent.
If the solvent is water, then the solvate may suitably be
considered as a hydrate, for example, a hemihydrate, a monohydrate,
a dihydrate, a trihydrate, etc.
For example, the solvates and/or hydrates may be obtained directly
at the end of the synthetic process, the target compound being
isolated in the form of a hydrate, for example a monohydrate or
hemihydrate, or in the form of a solvate of the reaction solvent
and/or purification solvent.
Unless otherwise indicated, any reference to a compound according
to the invention also includes the solvate or the hydrate of the
corresponding compound.
Typical processes for the preparation and identification of
hydrates and solvates are well known to those skilled in the art:
see, for example, pages 202-209 of K J Guillory, "Generation of
Polymorphs, Hydrates, Solvates, and Amorphous Solids" in
Polymorphism in Pharmaceutical Solids, edition. Harry G. Britain,
Vol. 95, Marcel Dekker, Inc., New York, 1999.
The hydrates and solvates may be isolated and characterized via
methods known in the art, such as thermogravimetric analysis (TGA),
TGA-mass spectroscopy, TGA-infrared spectroscopy, x-ray powder
diffraction, Karl Fischer titration, high-resolution x-ray
diffraction, and the like.
Preferably, the compound(s) of formula (Ia) are chosen from the
compounds as described in the tables below, and also the
pharmaceutically acceptable addition salts thereof, hydrates
thereof and/or solvates thereof:
TABLE-US-00001 TABLE 1 IC50 IC50 hRORg hCD4/IL17 ##STR00008##
1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid
(4-ethylphenyl)(1- ethylpropyl)amide Compound 1 B B ##STR00009##
1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid
((R)-sec-butyl)(4- ethylphenyl)amide Compound 2 B ND ##STR00010##
1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid
cyclopropyl(4- ethylphenyl)amide Compound 3 C ND ##STR00011##
3-bromo-1- (tetrahydropyran-2- yl)-1H-indazole-6- sulfonic acid (4-
ethylphenyl) isobutylamide Compound 4 C ND ##STR00012##
1-(tetrahydropyran-4- ylmethyl)-1H- indazole-5-sulfonic acid (4-
ethylphenyl)(tetrahy- dropyran-4- ylmethyl)amide Compound 5 C ND
##STR00013## 1-((3,5- dimethylisoxazol-4- yl)methyl)-N-(4-
ethylphenyl)-N- isobutyl-1H-indazole- 5-sulfonamide Compound 6 B ND
##STR00014## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid butyl(4- isopropylphenyl)amide Compound 7
B ND ##STR00015## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (4- ethylphenyl)propyl Compound 8 C ND
##STR00016## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid butyl(4- ethylphenyl)amide Compound 9 C ND
##STR00017## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (5-chloro-2- fluorophenyl) isobutylamide
Compound 10 C ND ##STR00018## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (2,5- dimethylphenyl) isobutylamide
Compound 11 B ND ##STR00019## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (3- methoxypyridin-2- yl)isobutylamide
Compound 12 C ND ##STR00020## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (4-butyl-2- methylphenyl) isobutylamide
Compound 13 B ND ##STR00021## N-(4-ethylphenyl)-N- isobutyl-1-
((tetrahydro-2H-pyran- 4-yl)methyl)-1H- indazole-5- sulfonamide
Compound 14 C ND ##STR00022## 3-amino-1H-indazole- 5-sulfonic acid
(4- ethylphenyl) isobutylamide Compound 15 C ND ##STR00023##
1-(tetrahydropyran-4- ylmethyl)-lH- indazole-5-sulfonic acid (4-
ethylphenyl)oxetan-3- ylmethylamide Compound 16 C ND ##STR00024##
1-(1-acetylpyrrolidin- 3-yl)-1H-indazole-5- sulfonic acid (4-
ethylphenyl) isobutylamide Compound 17 B ND ##STR00025##
3-(tetrahydropyran-4- ylmethoxy)-1- (tetrahydropyran-4-
ylmethyl)-1H- indazole-5-sulfonic acid (4- ethylphenyl)
isobutylamide Compound 18 C ND ##STR00026## 1-(3,5-
dimethylisoxazol-4- ylmethyl)-1H- indazole-5-sulfonic acid (4-
ethylphenyl) isobutylamide Compound 19 C ND ##STR00027##
1-((1-acetylpyrrolidin- 3-yl)methyl)-N-(4- ethylphenyl)-N-
isobutyl-1H-indazole- 5-sulfonamide Compound 20 C ND ##STR00028##
N-(4-ethylphenyl)-N- isobutyl-1- ((tetrahydrofuran-3-
yl)methyl)-1H- indazole-5- sulfonamide Compound 21 C ND
##STR00029## N-(4-ethylphenyl)-N- isobutyl-1-
((tetrahydro-2H-pyran- 3-yl)methyl)-1H- indazole-5- sulfonamide
Compound 22 C ND ##STR00030## 1-benzyl-N-(4- ethylphenyl)-N-
isobutyl-1H-indazole- 5-sulfonamide Compound 23 C ND ##STR00031##
N-(cyclobutylmethyl)- N-(4-ethylphenyl)-1- ((tetrahydro-2H-pyran-
4-yl)methyl)-1H- indazole-5- sulfonamide Compound 24 B ND
##STR00032## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (3- methoxyphenyl) isobutylamide Compound
25 C ND ##STR00033## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (3- methylphenyl) isobutylamide Compound
26 C ND ##STR00034## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (2,4- dimethylphenyl) isobutylamide
Compound 27 B ND ##STR00035## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (3,5- dimethylphenyl) isobutylamide
Compound 28 C ND ##STR00036## N-(4-ethylphenyl)-N- isopropyl-1-
((tetrahydro-2H-pyran- 4-yl)methyl)-1H- indazole-5- sulfonamide
Compound 29 C ND ##STR00037## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid sec-butyl(4- ethylphenyl)amide Compound 30
B ND ##STR00038## N- (cyclopropylmethyl)- N-(4-ethylphenyl)-1-
((tetrahydro-2H-pyran- 4-yl)methyl)-1H- indazole-5- sulfonamide
Compound 31 C ND ##STR00039## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid cyclopentyl(4- ethylphenyl)amide Compound
32 A ND ##STR00040## 1-(tetrahydropyran-4- ylmethyl)-1H-
indazole-5-sulfonic acid (4- ethylphenyl)(tetrahy- drofuran-3-
ylmethyl)amide Compound 33 C ND ##STR00041## 3-amino-1H-indazole-
5-sulfonic acid (4- ethylphenyl) isobutylamide Compound 34 C ND
##STR00042## N-(4-ethylphenyl)-N- isopentyl-1-
((tetrahydro-2H-pyran- 4-yl)methyl)-1H- indazole-5- sulfonamide
Compound 35 C ND ##STR00043## N-(4-ethylphenyl)-N-
isobutyl-1-(pyridin-4- ylmethyl)-1H- indazole-5- sulfonamide
Compound 36 B A ##STR00044## N-(4-ethylphenyl)-N-
isobutyl-1-(oxetan-3- ylmethyl)-1H- indazole-5- sulfonamide
Compound 37 B A ##STR00045## 1-(tetrahydropyran-4-
yl)-1H-indazole-5- sulfonic acid (4- ethylphenyl) isobutylamide
Compound 38 C ND ##STR00046## N-(4-ethylphenyl)-N- isobutyl-1-
((tetrahydro-2H-pyran- 4-yl)methyl)-1H- indazole-5- sulfonamide
Compound 39 B B
TABLE-US-00002 TABLE 2 IC50 IC50 hRORg hCD4/IL17 ##STR00047##
1-(1-acetylpyrrolidin-3-yl)- 1H-indazole-5-sulfonic acid (4-
ethylphenyl)isobutylamide Compound 40 C ND ##STR00048##
1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid
cyclobutyl(4- ethylphenyl)amide Compound 41 C ND ##STR00049##
1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid
(5-fluoro-2- methylphenyl)isobutylamide Compound 42 B ND
##STR00050## 1-(tetrahydropyran-4- ylmethyl)-2H-indazole-5-
sulfonic acid (3-fluoro-2- methylphenyl)isobutylamide Compound 43 B
ND ##STR00051## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (5- chlorophenyl)isobutylamide Compound 44 C ND
##STR00052## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (2- chlorophenyl)isobutylamide Compound 45 C ND
##STR00053## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (4- fluorophenyl)isobutylamide Compound 46 C ND
##STR00054## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid isobutyl-p- tolylamide Compound 47 C ND ##STR00055##
1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid
isobutyl-o- tolylamide Compound 48 C ND ##STR00056##
1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid (4-
trifluoromethoxyphenyl) isobutylamide Compound 49 C ND ##STR00057##
1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid
isobutyl(5- isopropylpyridin-2-yl)amide Compound 50 C ND
##STR00058## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (3- chlorobenzyl)isobutylamide Compound 51 C ND
##STR00059## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid isobutyl(2- trifluoromethylbenzyl)amide Compound 52 B
ND ##STR00060## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (2-fluoro-6- methylphenyl)isobutylamide Compound 53 C
ND ##STR00061## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (4-fluoro-2- methylphenyl)isobutylamide Compound 54 B
ND ##STR00062## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid isobutyl(4- methoxy-2- methylphenyl)amide Compound 55
B ND ##STR00063## methyl 4-{isobutyl[1- (tetrahydropyran-4-
ylmethyl)-1H-indazole-5- sulfonyl]amino}-3- methylbenzoate Compound
56 B A ##STR00064## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (4-cyano-2- methylphenyl)isobutylamide Compound 57 B
ND ##STR00065## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid isobutyl(2- trifluoromethylphenyl)amide Compound 58 B
ND ##STR00066## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid isobutyl(4- trifluoromethylphenyl)amide Compound 59 C
ND ##STR00067## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (3-chloro-2- hydroxymethylpropyl)(4-
ethylphenyl)amide Compound 60 C ND ##STR00068##
3-(tetrahydropyran-4- ylmethoxy)-1H-indazole-5- sulfonic acid (4-
ethylphenyl)isobutylamide Compound 61 C ND ##STR00069##
3-(tetrahydropyran-4- ylidenemethyl)-1H- indazole-6-sulfonic acid
(4- ethylphenyl)isobutylamide Compound 62 A ND ##STR00070##
3-(tetrahydropyran-4- ylmethyl)-1H-indazole-6- sulfonic acid (4-
ethylphenyl)isobutylamide Compound 63 A A ##STR00071##
3-morpholin-4-ylmethyl- 1H-indazole-6-sulfonic acid (4-
ethylphenyl)isobutylamide Compound 64 A A ##STR00072##
3-((cis)-2,6- dimethylmorpholin-4- ylmethyl)-1H-indazole-6-
sulfonic acid (4- ethylphenyl)isobutylamide Compound 65 C ND
##STR00073## 3-((S)-3-methylmorpholin- 4-ylmethyl)-1H-indazole-6-
sulfonic acid (4- ethylphenyl)isobutylamide Compound 66 B ND
##STR00074## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid isobutyl-o- tolylamide Compound 69 C ND ##STR00075##
1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5- sulfonic acid
(2-cyano-4- methylphenyl)isobutylamide Compound 70 B ND
##STR00076## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (4,6- dimethylpyridin-3- yl)isobutylamide Compound 71
C C ##STR00077## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (4- dimethylaminophenyl) isobutylamide Compound 72 B
B ##STR00078## 1-(tetrahydropyran-4- ylmethyl)-1H-indazole-5-
sulfonic acid (2-fluoro-4- methylphenyl)isobutylamide Compound 73
ND ND ##STR00079## methyl 5-[(4- ethylphenyl)isobutyl-
sulfamoyl]-1- (tetrahydropyran-4- ylmethyl)-1H-indazole-
7-carboxylate Compound 74 C ND ##STR00080## 5-[(4-
ethylphenyl)isobutyl- sulfamoyl]-1- (tetrahydropyran-4-
ylmethyl)-1H-indazole- 7-carboxylic acid amide Compound 75 ND ND
ND: not determined; A: IC50 <100 nM.; B: IC50 = 100 nM-1 .mu.M;
C: IC50 >1 .mu.M
In the tables described above, the median inhibitory concentrations
IC.sub.50 for the compounds belonging to formula (I) according to
the invention have been given according to the following
models:
GAL4-ROR.gamma. Transactivation
The ROR.gamma. transactivation model was developed from the line
HG5LN, which is a HeLa line that stably expresses a luciferase
reporter gene controlled by a pentamer of the GAL4 recognition
domain of yeast and of a .beta.-globin promoter. The HG5LN line was
stably transfected by the DNA-binding domain (DBD) of GAL4 fused to
the ROR gamma ligand-binding domain (LBD). Molecules that inhibit
the ROR gamma constitutive activity reduce the luciferase
expression, thus leading to a reduction in the emitted
luminescence.
The cells are seeded in 384-well plates (5000 cells in 45
.mu.L/well of culture medium containing 10% fetal calf serum) and
incubated for 4 hours at 37.degree. C., 5% CO.sub.2. 5 .mu.L of the
test molecules (compounds described in the tables described above)
are then added to each well and the plates are incubated for 18
hours at a temperature of 37.degree. C. under 5% of CO.sub.2. 20
.mu.L of luciferase substrate (Promega) are added to each well and
the luminescence emitted is read by a microplate reader.
The luminescence units ("RLU") are normalized by positive controls
("POS" containing a saturated concentration of
N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluorometh-
yl)ethyl]phenyl])benzenesulfonamide and negative controls ("NEG"
containing DMSO): % inhibition=((RLU-NEG)*100)/(POS-NEG). The IC50
values are calculated from a 4-parameter logistic model using the
XLFit software (IDBS).
IL-17A Secretion
This model allows measurement of the effect of inhibitors on IL-17A
secretion by CD4+ cells. The cells are frozen CD4+ cells (STEMCELL,
#70026), isolated from peripheral human blood and activated with
anti-CD3 and anti-CD28 antibodies. The amount of IL-17a secreted is
measured by the TR-FRET (kit HTRF.RTM. Human Interleukin 17A
(Cisbio, #64H17PEC)) technology.
The cells are rapidly thawed, resuspended in their culture medium
(RPMI inactivated 10% FCS) supplemented with soluble anti-CD28
antibodies and seeded (100 000 cells/well) in 96-well plates
precoated with anti-CD3 antibodies. The cells are then treated with
the ranges of inhibitors to be tested (from 1000 nM to 0.05 nM,
0.1% DMSO). After 4 days of incubation, the HTRF signal is measured
using a microplate reader (.lamda.excitation=337 nm,
.lamda.emission=620/665 nm). The ratios obtained (665/620) are
normalized relative to the positive control (cells activated with
anti-CD3 and anti-CD28, 0.1% DMSO). The IC.sub.50 values are
calculated from a 4-parameter logistic model using the XLFit
software (IDBS).
Preferentially, the compounds of formula (I) according to the
invention are chosen from the following compounds:
TABLE-US-00003 TABLE 3 ##STR00081## N-(4-ethylphenyl)-N-isobutyl-1-
((tetrahydro-2H-pyran-4-yl)methyl)-1H- indazole-5-sulfonamide
Compound 39 ##STR00082## N-(4-ethylphenyl)-N-isobutyl-1-
(oxetan-3-ylmethyl)-1H-indazole-5- sulfonamide Compound 37
##STR00083## 1-((1-acetylpyrrolidin-3-yl)methyl)-N-
(4-ethylphenyl)-N-isobutyl-1H- indazole-5-sulfonamide Compound 20
##STR00084## 1-((3,5-dimethylisoxazol-4-yl)methyl)-
N-(4-ethylphenyl)-N-isobutyl-1H- indazole-5-sulfonamide Compound 24
##STR00085## 1-(1-acetylpyrrolidin-3-yl)-1H-indazole- 5-sulfonic
acid (4- ethylphenyl)isobutylamide Compound 40 ##STR00086##
N-(cyclobutylmethyl)-N-(4- ethylphenyl)-1-((tetrahydro-2H-pyran-4-
yl)methyl)-1H-indazole-5-sulfonamide Compound 24 ##STR00087##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
cyclopentyl(4- ethylphenyl)amide Compound 32 ##STR00088##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
sec-butyl(4- ethylphenyl)amide Compound 30 ##STR00089##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
ethylphenyl)(1-ethylpropyl)amide Compound 1 ##STR00090##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
butyl(4- isopropylphenyl)amide Compound 7 ##STR00091##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(5-fluoro-2- methylphenyl)isobutylamide Compound 42 ##STR00092##
1-(tetrahydropyran-4-ylmethyl)-2H- indazole-5-sulfonic acid
(3-fluoro-2- methylphenyl)isobutylamide Compound 43 ##STR00093##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,5-
dimethylphenyl)isobutylamide Compound 11 ##STR00094##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(4-butyl-2- methylphenyl)isobutylamide Compound 13 ##STR00095##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,4-
dimethylphenyl)isobutylamide Compound 27 ##STR00096##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl(2- trifluoromethylbenzyl)amide Compound 52 ##STR00097##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(4-fluoro-2- methylphenyl)isobutylamide Compound 54 ##STR00098##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl(4- methoxy-2-methylphenyl)amide Compound 55 ##STR00099##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(4-cyano-2- methylphenyl)isobutylamide Compound 57 ##STR00100##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl(2- trifluoromethylphenyl)amide Compound 58 ##STR00101##
3-(tetrahydropyran-4-ylmethyl)-1H- indazole-6-sulfonic acid (4-
ethylphenyl)isobutylamide Compound 63 ##STR00102##
3-morpholin-4-ylmethyl-1H-indazole-6- sulfonic acid (4-
ethylphenyl)isobutylamide Compound 64 ##STR00103##
3-((S)-3-methylmorpholin-4-ylmethyl)- 1H-indazole-6-sulfonic acid
(4- ethylphenyl)isobutylamide Compound 66
In particular, among the compounds of formula (II), compounds 1, 2,
7, 11, 21, 24, 27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57
and 58 are preferred.
Among the compounds of formula (III), compounds 63, 64 and 66 are
preferred.
The invention also relates to the compound(s) as described
previously, as medicament and cosmetic.
Preferably, the invention also relates to the compound(s) as
described previously, as medicament.
Specifically, the compounds according to the invention have
advantageous pharmacological properties, given that said compounds
modulate, i.e. inhibit, the activity of the ROR.gamma.t
receptor.
Thus, these properties make the compound(s) of formula (I) as
described previously usable as medicament in the treatment of
diseases mediated by the ROR.gamma.t receptor.
Preferably, the compound(s) according to the invention are used in
the treatment of inflammatory disorders and/or autoimmune diseases
mediated by the ROR.gamma.t receptor.
More preferentially, the compound(s) according to the invention,
preferably those chosen from the compounds corresponding to
formulae (II) and (III), are used in the treatment of acne,
psoriasis and/or atopic dermatitis.
According to another embodiment, the compounds according to the
invention are used for cosmetic treatment of the skin.
As indicated above, the present invention also relates to a
pharmaceutical composition comprising, in a pharmaceutically
acceptable medium, one or more compounds of formula (I) as defined
previously, pharmaceutically acceptable addition salts thereof,
hydrates thereof and/or solvates thereof.
Preferably, the pharmaceutical composition comprises one or more
compounds chosen from the compounds of formulae (II) and (III) as
defined previously, the pharmaceutically acceptable addition salts
thereof, hydrates thereof and/or solvates thereof.
More preferentially, the pharmaceutical composition comprises one
or more compounds of formula (I) chosen from compounds (1) to (75)
defined previously.
Even more preferentially, the pharmaceutical composition comprises
one or more compounds of formula (I) chosen from compounds 1, 2, 7,
11, 21, 24, 27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57, 58,
63, 64 and 66.
The pharmaceutical composition according to the invention as
described previously may be administered orally or topically.
Preferably, the pharmaceutical composition is conditioned in a form
that is suitable for topical application.
Via the oral route, the composition may be in the form of tablets,
gel capsules, coated tablets, syrups, suspensions, solutions,
powders, granules, emulsions, suspensions of microspheres or
nanospheres or lipid or polymeric vesicles allowing controlled
release.
Via the topical route, the pharmaceutical composition according to
the invention is more particularly intended for treating the skin
and mucous membranes, and may be in liquid, pasty or solid form,
and more particularly in the form of ointments, creams, milks,
pomades, powders, impregnated pads, syndets, solutions, gels,
sprays, mousses, suspensions, sticks, shampoos or washing bases. It
may also be in the form of suspensions of microspheres or
nanospheres or lipid or polymeric vesicles or of polymeric or
gelled patches allowing controlled release.
The pharmaceutical composition is used for treating inflammatory
disorders and/or autoimmune diseases mediated by the ROR.gamma.t
receptor.
More preferentially, the pharmaceutical composition is used in the
treatment of acne and/or psoriasis.
The invention also relates to a process for treating diseases
mediated by the ROR.gamma.t receptor, comprising the
administration, especially topically or orally, of a
therapeutically effective amount of the pharmaceutical composition
as defined above to a patient.
Preferably, the pharmaceutical composition is applied
topically.
In accordance with another embodiment, a subject of the present
invention is also one or more compounds of formula (II) as defined
previously, the pharmaceutically acceptable addition salts thereof,
hydrates thereof and/or solvates thereof:
##STR00104##
in which formula (II) R.sup.1, R.sup.3, R.sup.5 and Y.sup.1 to
Y.sup.5 have the same meanings as in formula (Ia) described
previously.
Preferably, R.sup.3 represents a group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7 with
R.sup.7 representing a non-cationic heterocyclic radical, a
non-cationic cycloalkyl radical or a non-cationic aromatic or
heteroaromatic radical as defined previously.
Among the compounds of formula (II), compounds 1, 2, 7, 11, 21, 24,
27, 30, 32, 36, 37, 39, 40, 42, 43, 52, 54, 55, 57 and 58 are
preferred.
According to this embodiment, the invention also relates to the
compound(s) of formula (II), as medicament and cosmetic.
In particular, the invention relates to the compound(s) of formula
(II), for their use in the treatment of inflammatory disorders
and/or autoimmune diseases mediated by the ROR.gamma.t
receptor.
Preferentially, a subject of the invention is the compound(s) of
formula (II) for their use in the treatment of acne.
As a variant, a subject of the invention is also the compound(s) of
formula (II) for their use in the treatment of psoriasis.
Alternatively, the compound(s) of formula (II) according to the
invention are used for cosmetic treatment of the skin.
Furthermore, the invention also relates to a pharmaceutical
composition comprising, in a pharmaceutically acceptable medium,
one or more compounds of formula (II) as defined previously,
pharmaceutically acceptable addition salts thereof, hydrates
thereof and/or solvates thereof.
The pharmaceutical composition is used for treating inflammatory
disorders and/or autoimmune diseases mediated by the ROR.gamma.t
receptor.
In accordance with another embodiment, a subject of the present
invention is also one or more compounds of formula (III) as defined
previously, the pharmaceutically acceptable addition salts thereof,
hydrates thereof and/or solvates thereof:
##STR00105##
in which formula (III) R.sup.1, R.sup.3, R.sup.5 and Y.sup.1 to
Y.sup.5 have the same meanings as in formula (I) described
previously.
Preferably, R.sup.3 represents a group
(CHR.sup.6).sub.n--(Z).sub.o--(CHR'.sup.6).sub.p--R.sup.7 with
R.sup.7 representing a non-cationic heterocyclic radical, a
non-cationic cycloalkyl radical or a non-cationic aromatic or
heteroaromatic radical as defined previously.
Among the compounds of formula (III), compounds 63, 64 and 66 are
preferred.
According to this embodiment, the invention also relates to the
compound(s) of formula (III), as medicament and cosmetic.
In particular, the invention relates to the compound(s) of formula
(III), for their use in the treatment of inflammatory disorders
and/or autoimmune diseases mediated by the ROR.gamma.t
receptor.
Preferentially, a subject of the invention is the compound(s) of
formula (III) for their use in the treatment of acne.
As a variant, a subject of the invention is also the compound(s) of
formula (III) for their use in the treatment of psoriasis.
Alternatively, the compound(s) of formula (III) according to the
invention are used for cosmetic treatment of the skin.
Furthermore, the invention also relates to a pharmaceutical
composition comprising, in a pharmaceutically acceptable medium,
one or more compounds of formula (III) as defined previously,
pharmaceutically acceptable addition salts thereof, hydrates
thereof and/or solvates thereof.
The pharmaceutical composition is used for treating inflammatory
disorders and/or autoimmune diseases mediated by the ROR.gamma.t
receptor.
The examples that follow serve to illustrate the invention without,
however, being limiting in nature.
EXAMPLES
The standard LCMS method for analyzing the products is as follows:
BEH C.sub.18 standard column (150.times.2.1 mm, 1.8 .mu.m) solvent:
water/acetonitrile 0.1% formic acid.
The preparative HPLC purifications were performed on a C.sub.18
column using, as eluent: 85% acetonitrile in water/0.1% formic
acid.
Part I: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme
1
##STR00106##
Example 1: Synthesis of
N-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-inda-
zole-5-sulfonamide
##STR00107##
1. Synthesis of Intermediate 1.1
##STR00108##
(4-ethylphenyl)isobutylamine
Isobutyraldehyde (6.33 ml; 0.07 mol) in tetrahydrofuran (100 ml) is
added to 4-ethylaniline (9.48 ml; 0.08 mol). The mixture is stirred
for 2 hours at room temperature. Sodium triacetoxyborohydride
(22.04 g; 0.10 mol) is then added. The mixture is stirred overnight
at room temperature, water (100 ml) are added and the resulting
mixture is extracted with ethyl acetate (2.times.100 ml). The
organic phases are combined, washed with brine (100 ml), dried
(Na.sub.2SO.sub.4) and concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/dichloromethane from 0 to 50% of dichloromethane). The
(4-ethylphenyl)isobutylamine is obtained in the form of an orange
oil with a compliant .sup.1H NMR.
MS: [M+H]=179
2. Synthesis of Intermediate 1.2
##STR00109##
N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide
1H-Indazole-5-sulfonyl chloride (502 mg; 2.20 mmol) is added to
(4-ethylphenyl)isobutylamine (300 mg; 1.69 mmol) and pyridine (820
.mu.l; 10.15 mmol) in tetrahydrofuran (6 ml). The reaction medium
is stirred for 7 hours at room temperature, hydrolyzed and
extracted with ethyl acetate. The organic phases are combined,
washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 20 to 50% of ethyl acetate). The
N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (357 mg;
59%) is obtained in the form of a cream-colored solid with a
compliant .sup.1H NMR.
MS: [M+H]=358
3. Synthesis of Compound 39 According to the Invention
##STR00110##
4-(Bromomethyl)tetrahydropyran (90 mg; 0.50 mmol) is added to
N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (150 mg;
0.42 mmol) and cesium carbonate (137 mg; 0.42 mmol) in
N,N-dimethylformamide (12 ml). The reaction medium is stirred for
30 minutes at a temperature of 100.degree. C. under microwave
irradiation, hydrolyzed and extracted with ethyl acetate. The
organic phases are combined, washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, 40% of ethyl acetate). The
N-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-inda-
zole-5-sulfonamide (97 mg; 50%) is obtained in the form of a white
powder.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 0.85 (d, J=6.6 Hz, 7H), 1.17
(t, J=7.6 Hz, 4H), 1.22-1.53 (m, 6H), 2.16-2.31 (m, 1H), 2.59 (q,
J=7.6 Hz, 2H), 3.15-3.44 (m, 6H), 3.83 (ddd, J=11.5, 4.4, 2.0 Hz,
3H), 4.39 (d, J=7.2 Hz, 3H), 6.92-7.05 (m, 3H), 7.10-7.21 (m, 3H),
7.26 (dd, J=9.1, 1.8 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 8.10 (d,
J=1.7 Hz, 1H), 8.62 (s, 1H).
MS: [M+H]=456
With a procedure similar to that described for the synthesis of
example 1, the compounds of the table below are obtained:
TABLE-US-00004 Example 2 ##STR00111##
N-(4-ethylphenyl)-N-isobutyl-1-
((tetrahydro-2H-pyran-3-yl)methyl)-1H- indazole-5-sulfonamide 1H
NMR (DMSO-d6) .delta.: 0.85 (d, J = 6.6 Hz, 6H), 1.17 (t, J = 7.6
Hz, 3H), 1.23-1.35 (m, 1H), 1.35-1.53 (m, 2H), 1.54-1.72 (m, 2H),
2.08-2.23 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 3.21 (dd, J = 11.2,
8.9 Hz, 1H), 3.32- 3.40 (m, 3H), 3.57-3.65 (m, 1H), 3.70 (dt, J =
10.9, 3.9 Hz, 1H), 4.31-4.48 (m, 2H), 6.96 (d, J = 8.3 Hz, 2H),
7.16 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 9.0, 1.8 Hz, 1H), 7.84-
7.89 (m, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 0.8 Hz, 1H)
MS: [M + H] = 456 Example 3 ##STR00112##
N-(4-ethylphenyl)-N-isobutyl-1- ((tetrahydrofuran-3-yl)methyl)-1H-
indazole-5-sulfonamide 1H NMR (DMSO-d6) .delta.: 0.85 (d, J = 6.7
Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.42 (hept, J = 6.8 Hz, 1H),
1.57-1.73 (m, 1H), 1.83-2.00 (m. 1H), 2.60 (q, J = 7.6 Hz, 2H),
2.81 (hept, J = 7.1 Hz, 1H), 3.31-3.35 (m, 2H), 3.50 (dd, J = 8.6,
5.6 Hz, 1H), 3.60-3.71 (m, 2H), 3.81 (td, J = 8.1, 5.5 Hz, 1H),
4.36- 4.55 (m, 2H), 6.96 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.3 Hz,
2H), 7.46 (dd, J = 8.8, 1.8 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 8.09
(d, J = 1.7 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 442
Example 4 ##STR00113## N-(4-ethylphenyl)-N-isobutyl-1-(oxetan-3-
ylmethyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) .delta.: 0.85
(d, J = 6.6 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.41 (non, J = 6.8
Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.32 (m, 2H), 3.52 (tt, J = 7.6,
6.1 Hz, 1H), 4.49 (t, J = 6.2 Hz, 2H), 4.67 (dd, J = 7.8, 6.1 Hz,
2H), 4.77 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 7.17 (d, J
= 8.3 Hz, 2H), 7.47 (dd, J = 8.9, 1.7 Hz, 1H), 7.91 (d, J = 8.9 Hz,
1H), 8.09 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H) MS: [M + H]
= 428 Example 5 ##STR00114##
1-((1-acetylpyrrolidin-3-yl)methyl)-N-(4-
ethylphenyl)-N-isobutyl-1H-indazole-5- sulfonamide 1H NMR (DMSO-d6,
80.degree. C.) .delta.: 0.86 (d, J = 6.6 Hz, 6H), 1.19 (t, J = 7.6
Hz, 3H), 1.44- 1.60 (m, 1H), 1.60-1.83 (m, 1H), 1.83- 2.07 (m, 4H),
2.61 (q, J = 7.6 Hz, 2H), 2.72- 2.94 (m, 1H), 3.09-3.61 (m, 6H),
4.51 (d, J = 7.1 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 7.16 (d, J =
8.1 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H),
8.10 (s, 1H), 8.28 (s, 1H) MS: [M + H] = 483 Example 6 ##STR00115##
1-benzyl-N-(4-ethylphenyl)-N-isobutyl-1H- indazole-5-sulfonamide 1H
NMR (DMSO-d6) .delta.: 0.84 (d, J = 6.7 Hz, 6H), 1.16 (t, J = 7.6
Hz, 3H), 1.41 (hept, J = 6.9 Hz, 1H), 2.59 (q, J = 7.6 Hz, 2H),
3.32 (m, 2H), 5.71 (s, 2H), 6.98 (d, J = 8.4 Hz, 2H), 7.16 (d, J =
8.4 Hz, 2H), 7.25 (dd, J = 9.2, 1.8 Hz, 1H), 7.31-7.43 (m, 5H),
7.73 (d, J = 9.1 Hz, 1H), 8.12 (dd, J = 1.9, 0.8 Hz, 1H), 8.75 (d,
J = 1.0 Hz, 1H) MS: [M + H] = 448 Example 7 ##STR00116##
N-(4-ethylphenyl)-N-isobutyl-1-(pyridin-4-
ylmethyl)-1H-indazole-5-sulfonamide 1H NMR (DMSO-d6) .delta.: 0.85
(d, J = 6.6 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 1.32-1.48 (m, 1H),
2.59 (q, J = 7.7 Hz, 2H), 3.33 (m, 2H), 5.82 (s, 2H), 6.96 (d, J =
7.9 Hz, 2H), 7.15 (dd, J = 11.8, 6.5 Hz, 4H), 7.48 (d, J = 8.9 Hz,
1H), 7.90 (d, J = 8.9 Hz, 1H), 8.14 (s, 1H), 8.39 (s, 1H), 8.52 (d,
J = 5.1 Hz, 2H) MS: [M + H] = 449 Example 8 ##STR00117##
1-((3,5-dimethylisoxazol-4-yl)methyl)-N-
(4-ethylphenyl)-N-isobutyl-1H-indazole-5- sulfonamide 1H NMR
(DMSO-d6) .delta.: 0.85 (d, J = 6.6 Hz, 6H), 1.17 (t, J = 7.6 Hz,
3H), 1.41 (hept, J = 6.8 Hz, 1H), 2.11 (s, 3H), 2.44 (s, 3H), 2.59
(q, J = 7.6 Hz, 2H), 3.33 (s, 2H), 5.54 (s, 2H), 6.88-7.00 (m, 2H),
7.12-7.20 (m, 2H), 7.50 (dd, J = 8.9, 1.8 Hz, 1H), 7.88-8.01 (m,
1H), 8.10 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H]
= 467
Example 9: Synthesis of
1-((1-acetylazetidin-3-yl)methyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00118##
1-(3-Hydroxymethylazetidin-1-yl)ethanone (0.27 g; 2.09 mmol) in
toluene (1 ml) is added to a mixture of
N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide (0.20 g;
0.56 mmol) and
(triphenyl-.lamda..sup.5-phosphanylidene)acetonitrile (0.51 g; 1.68
mmol) in anhydrous toluene (3 ml) under argon. The reaction medium
is stirred for 3 days at a temperature of 95.degree. C., hydrolyzed
and extracted with ethyl acetate. The organic phase is washed,
dried (Na.sub.2SO.sub.4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1-(1-acetylazetidin-3-ylmethyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide (136 mg; 51%) is obtained in the form
of a pale yellow solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t,
J=7.6 Hz, 3H), 1.42 (hept, J=6.8 Hz, 1H), 1.73 (s, 3H), 2.59 (q,
J=7.6 Hz, 2H), 3.07-3.20 (m, 1H), 3.30-3.36 (m, 2H), 3.69 (dd,
J=9.6, 5.6 Hz, 1H), 3.89 (t, J=9.0 Hz, 1H), 3.98 (dd, J=8.5, 5.5
Hz, 1H), 4.18 (t, J=8.4 Hz, 1H), 4.71 (d, J=7.3 Hz, 2H), 6.96 (d,
J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.48 (dd, J=9.0, 1.7 Hz,
1H), 7.89-7.97 (m, 1H), 8.09 (d, J=1.7 Hz, 1H), 8.31 (d, J=0.9 Hz,
1H)
MS: [M+H]=469
Example 10: Synthesis of
1-(tetrahydropyran-4-yl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00119##
By following the same procedure as that for example 9,
1-(tetrahydropyran-4-yl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide (22 mg; 36%) is obtained in the form
of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t,
J=7.6 Hz, 3H), 1.41 (non, J=6.5 Hz, 1H), 1.85-1.97 (m, 2H), 2.15
(qd, J=12.3, 4.6 Hz, 2H), 2.60 (q, J=7.6 Hz, 2H), 3.30-3.32 (m,
2H), 3.58 (td, J=11.9, 2.0 Hz, 2H), 3.98-4.07 (m, 2H), 4.99 (td,
J=11.3, 5.7 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz,
2H), 7.44 (dd, J=8.9, 1.7 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 8.11 (d,
J=1.6 Hz, 1H), 8.32 (s, 1H)
MS: [M+H]=442
Example 11: Synthesis of
1-(1-acetylpyrrolidin-3-yl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00120##
A mixture of N-(4-ethylphenyl)-N-isobutyl-1H-indazole-5-sulfonamide
(0.20 g; 0.56 mmol), cesium carbonate (0.27 g; 0.84 mmol) and
1-(3-bromopyrrolidin-1-yl)ethanone (0.13 g; 0.67 mmol) in
1-methyl-2-pyrrolidone (3 ml) is stirred for 5 hours at a
temperature of 80.degree. C., hydrolyzed and extracted with ethyl
acetate. The organic phase is washed with water, dried
(Na.sub.2SO.sub.4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1-(1-acetylpyrrolidin-3-yl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide (29 mg; 11%) is obtained in the form
of a white solid.
Mixture of two conformers: .sup.1H NMR (DMSO-d6) .delta.: 0.85 (dd,
J=6.7, 1.1 Hz, 6H), 1.18 (t, J=7.6 Hz, 3H), 1.33-1.50 (m, 1H), 2.01
(s, 3H), 2.60 (q, J=7.6 Hz, 2H), 3.34 (d, J=2.4 Hz, 2H), 3.46-3.54
(m, 1H), 3.59-3.65 (m, 1H), 3.65-3.72 (m, 1H), 3.76-3.82 (m, 1H),
3.85 (dd, J=12.3, 6.8 Hz, 1H), 4.05 (dd, J=10.8, 7.0 Hz, 1H), 5.57
(ddt, J=27.8, 11.5, 6.2 Hz, 1H), 6.90-7.03 (m, 2H), 7.16-7.21 (m,
2H), 7.49 (ddd, J=8.8, 5.4, 1.7 Hz, 1H), 7.92 (t, J=9.0 Hz, 1H),
8.11 (dd, J=3.4, 1.6 Hz, 1H), 8.32-8.41 (m, 1H)
MS: [M+H]=469
With a procedure similar to that for intermediate 1.1,
corresponding to a reductive amination between 1 equivalent of
aldehyde and 1.15 equivalents of aniline in tetrahydrofuran in the
presence of 1.45 equivalents of sodium triacetoxyborohydride, the
anilines of the table below are obtained:
TABLE-US-00005 Intermediate 12.1 ##STR00121## cyclopropylmethyl(4-
ethylphenyl)amine (300 mg; 46%) obtained in the form of an orange
oil with a compliant .sup.1H NMR. MS: [M + H] = 176 Intermediate
13.1 ##STR00122## cyclobutylmethyl(4- ethylphenyl)amine (400 mg;
56%) obtained in the form of an orange oil with a compliant .sup.1H
NMR. MS: [M + H] = 190 Intermediate 14.1 ##STR00123##
cyclopentylmethyl(4- ethylphenyl)amine (19.3 g; 56%) obtained in
the form of an amber-colored oil with a compliant .sup.1H NMR. MS:
[M + H] = 190 Intermediate 15.1 ##STR00124## cyclobutylmethyl(4-
ethylphenyl)amine (700 mg; 97%) obtained in the form of an oil with
a compliant .sup.1H NMR. MS: [M + H] = 176 Intermediate 16.1
##STR00125## (tetrahydrofuran-3-ylmethyl)(4- ethylphenyl)amine (600
mg; 78%) obtained in the form of an orange oil with a compliant
.sup.1H NMR. MS: [M + H] = 206 Intermediate 17.1 ##STR00126##
sec-butyl(4-ethylphenyl)amine (600 mg; 90%) obtained in the form of
an orange oil with a compliant .sup.1H NMR. MS: [M + H] = 178
Intermediate 18.1 ##STR00127## (4-ethylphenyl)(3-methylbutyl)amine
(250 mg; 32%) obtained in the form of an orange oil with a
compliant .sup.1H NMR. MS: [M + H] = 192 Intermediate 19.1
##STR00128## 4-ethyl-N-isopropylaniline (300 mg; 49%) obtained in
the form of an orange oil with a compliant .sup.1H NMR. MS: [M + H]
= 165 Intermediate 20.1 ##STR00129##
(4-ethylphenyl)(1-ethylpropyl)amine (700 mg; 98%) obtained in the
form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 192
Intermediate 21.1 ##STR00130## ethyl(4-ethylphenyl)amine commercial
Intermediate 22.1 ##STR00131## propyl(4-ethylphenyl)amine (450 mg;
73%) obtained in the form of an oil with a compliant .sup.1H NMR.
MS: [M + H] = 165 Intermediate 23.1 ##STR00132##
butyl(4-ethylphenyl)amine (650 mg; 98%) obtained in the form of an
oil with a compliant .sup.1H NMR. MS: [M + H] = 178 Intermediate
24.1 ##STR00133## (2,2,2-trifluoroethyl)(4- ethylphenyl)amine
commercial Intermediate 25.1 ##STR00134##
isobutyl(4-isopropylphenyl)amine (600 mg; 93%) obtained in the form
of an oil with a compliant .sup.1H NMR. MS: [M + H] = 193
Intermediate 26.1 ##STR00135## (5-chloro-2-
fluorophenyl)isobutylamine (350 mg; 56%) obtained in the form of an
oil with a compliant .sup.1H NMR. MS: [M + H] = 202 Intermediate
27.1 ##STR00136## (5-fluoro-2- methylphenyl)isobutylamine (802 mg;
61%) obtained in the form of an oil with a compliant .sup.1H NMR.
MS: [M + H] = 182 Intermediate 28.1 ##STR00137## (3-fluoro-2-
methylphenyl)isobutylamine (408 mg; 31%) obtained in the form of an
oil with a compliant .sup.1H NMR. MS: [M + H] = 182 Intermediate
29.1 ##STR00138## (5-chlorophenyl)isobutylamine (655 mg; 100%)
obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M
+ H] = 185 Intermediate 30.1 ##STR00139##
(2-chlorophenyl)isobutylamine (655 mg; 100%) obtained in the form
of an oil with a compliant .sup.1H NMR. MS: [M + H] = 184
Intermediate 31.1 ##STR00140## (4-fluorophenyl)isobutylamine (684
mg; 100%) obtained in the form of an oil with a compliant .sup.1H
NMR. MS: [M + H] = 169 Intermediate 32.1 ##STR00141##
(4-methylphenyl)isobutylamine (876 mg; 63%) obtained in the form of
a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 164
Intermediate 33.1 ##STR00142## isobutyl-o-tolylamine (972.8 mg;
70%) obtained in the form of an oil with a compliant .sup.1H NMR.
MS: [M + H] = 164 Intermediate 34.1 ##STR00143##
(2,5-dimethylphenyl)isobutylamine (700 mg; 97%) obtained in the
form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 179
Intermediate 35.1 ##STR00144## (4-butyl-2-
methylphenyl)isobutylamine (520 mg; 85%) obtained in the form of a
clear yellow oil with a compliant .sup.1H NMR. MS: [M + H] = 220
Intermediate 36.1 ##STR00145## (2,4-dimethylphenyl)isobutylamine
(1.15 g; 83%) obtained in the form of an oil with a compliant
.sup.1H NMR. MS: [M + H] = 179 Intermediate 37.1 ##STR00146##
(3.5-dimethylphenyl)isobutylamine (600 mg; 82%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
179 Intermediate 38.1 ##STR00147## (3-methylphenyl)isobutylamine
(600 mg; 79%) obtained in the form of a colorless oil with a
compliant .sup.1H NMR. MS: [M + H] = 164 Intermediate 39.1
##STR00148## (3-methoxyphenyl)isobutylamine (600 mg; 82%) obtained
in the form of a colorless oil with a compliant .sup.1H NMR. MS: [M
+ H] = 181 Intermediate 40.1 ##STR00149## (4-
trifluoromethoxyphenyl)isobutylamine (600 mg; 100%) obtained in the
form of an oil with a compliant .sup.1H NMR. MS: [M + H] = 235
Intermediate 41.1 ##STR00150## isobutyl(5-isopropylpyridin-2-
yl)amine (600 mg; 93%) obtained in the form of an oil with a
compliant .sup.1H NMR. MS: [M + H] = 193 Intermediate 42.1
##STR00151## (3-methoxypyridin-2-yl)isobutylamine (450 mg; 68%)
obtained in the form of an oil with a compliant .sup.1H NMR. MS: [M
+ H] = 181 Intermediate 43.1 ##STR00152##
(3-chlorobenzyl)isobutylamine (500 mg; 68%) obtained in the form of
an oil with a compliant .sup.1H NMR. MS: [M + H] = 198 Intermediate
44.1 ##STR00153## (3-methoxypyridin-2-yl)isobutylamine (600 mg;
100%) obtained in the form of an oil with a compliant .sup.1H NMR.
MS: [M + H] = 232 Intermediate 45.1 ##STR00154## (2-fluoro-6-
methylphenyl)isobutylamine (560 mg; 44%) obtained in the form of an
oil with a compliant .sup.1H NMR. MS: [M + H] = 182 Intermediate
46.1 ##STR00155## (4-chloro-2- methylphenyl)isobutylamine (892 mg;
71%) obtained in the form of an oil with a compliant .sup.1H NMR.
MS: [M + H] = 182 Intermediate 47.1 ##STR00156##
isobutyl(4-methoxy-2- methylphenyl)amine (980 mg; 77%) obtained in
the form of an oil with a compliant .sup.1H NMR. MS: [M + H] =
193
With a procedure similar to that for intermediate 1.2, by reacting
1 equivalent of N-substituted anilines (derived from the above
table or corresponding commercial products) with 1.3 equivalents of
1H-indazole-5-sulfonyl chloride in tetrahydrofuran (20 vol) in the
presence of 6 equivalents of pyridine, the intermediates of the
table below are obtained:
TABLE-US-00006 Intermediate 12.2 ##STR00157##
1H-indazole-5-sulfonic acid cyclopropylmethyl(4- ethylphenyl)amide
(450 mg; 81%) is obtained in the form of colorless oil with a
compliant .sup.1H NMR. MS: [M + H] = 356 Intermediate 13.2
##STR00158## 1H-indazole-5-sulfonic acid cyclobutylmethyl(4-
ethylphenyl)amide (590 mg; 55%) obtained in the form of a colorless
oil with a compliant .sup.1H NMR. MS: [M + H] = 370 Intermediate
14.2 ##STR00159## 1H-indazole-5-sulfonic acid
cyclopentyl(4-ethylphenyl)amide (250 mg; 47%) obtained in the form
of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 370
Intermediate 15.2 ##STR00160## 1H-indazole-5-sulfonic acid
cyclobutyl(4-ethylphenyl)amide (80 mg; 51%) obtained in the form of
a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 356
Intermediate 16.2 ##STR00161## 1H-indazole-5-sulfonic acid (4-
ethylphenyl)(tetrahydrofuran-3- ylmethyl)amide (800 mg; 78%)
obtained in the form of a colorless oil with a compliant .sup.1H
NMR. MS: [M + H] = 386 Intermediate 17.2 ##STR00162##
1H-indazole-5-sulfonic acid sec- butyl(4-ethylphenyl)amide (310 mg;
56%) obtained in the form of a colorless oil with a compliant
.sup.1H NMR. MS: [M + H] = 358 Intermediate 18.2 ##STR00163##
1H-indazole-5-sulfonic acid (4- ethylphenyl)(3-methylbutyl)amide
(220 mg; 50%) obtained in the form of a colorless oil with a
compliant .sup.1H NMR. MS: [M + H] = 372 Intermediate 19.2
##STR00164## 1H-indazole-5-sulfonic acid (4-
ethylphenyl)isopropylamide (400 mg; 70%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR MS: [M + H] = 344
Intermediate 20.2 ##STR00165## 1H-indazole-5-sulfonic acid (4-
ethylphenyl)(1-ethylpropyl)amide (40 mg; 25%) obtained in the form
of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 372
Intermediate 21.2 ##STR00166## 1H-indazole-5-sulfonic acid ethyl(4-
ethylphenyl)amide (160 mg; 55%) obtained in the form of a colorless
oil with a compliant .sup.1H NMR. MS: [M + H] = 330 Intermediate
22.2 ##STR00167## 1H-indazole-5-sulfonic acid (4-
ethylphenyl)propylamide (400 mg; 46%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 344
Intermediate 23.2 ##STR00168## 1H-indazole-5-sulfonic acid (4-
ethylphenyl)butylamide (800 mg; 67%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 358
Intermediate 25.2 ##STR00169## 1H-indazole-5-sulfonic acid
isobutyl(4-isopropylphenyl)amide (800 mg; 76%) obtained in the form
of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 372
Intermediate 26.2 ##STR00170## 1H-indazole-5-sulfonic acid (5-
chloro-2-fluorophenyl)isobutylamide (120 mg; 20%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
381 Intermediate 27.2 ##STR00171## 1H-indazole-5-sulfonic acid (5-
fluoro-2-methylphenyl)isobutylamide (267 mg; 53%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
362 Intermediate 28.2 ##STR00172## 1H-indazole-5-sulfonic acid (3-
fluoro-2-methylphenyl)isobutylamide (137 mg; 38%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
362 Intermediate 29.2 ##STR00173## 1H-indazole-5-sulfonic acid
(5-chlorophenyl)isobutylamide (90 mg; 56%) obtained in the form of
a white solid with a compliant .sup.1H NMR. MS: [M + H] = 364
Intermediate 31.2 ##STR00174## 1H-indazole-5-sulfonic acid (4-
fluorophenyl)isobutylamide (100 mg; 66%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 348
Intermediate 32.2 ##STR00175## 1H-indazole-5-sulfonic acid
isobutyl- p-tolylamide (770 mg; 81%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR MS: [M + H] = 344
Intermediate 33.2 ##STR00176## 1H-indazole-5-sulfonic acid
isobutyl- o-tolylamide (481 mg; 46%) obtained in the form of a
white solid with compliant .sup.1H NMR. MS: [M + H] = 344
Intermediate 34.2 ##STR00177## 1H-indazole-5-sulfonic acid (2,5-
dimethylphenyl)isobutylamide (540 mg; 59%) obtained in the form of
a colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 358
Intermediate 35.2 ##STR00178## 1H-indazole-5-sulfonic acid
(4-butyl- 2-methylphenyl)isobutylamide (650 mg; 75%) obtained in
the form of a colorless oil with a compliant .sup.1H NMR. MS: [M +
H] = 400 Intermediate 36.2 ##STR00179## 1H-indazole-5-sulfonic acid
(2,4- dimethylphenyl)isobutylamide (500 mg; 55%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
381 Intermediate 37.2 ##STR00180## 1H-indazole-5-sulfonic acid
(3,5- dimethylphenyl)isobutylamide (140 mg; 13%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
358 Intermediate 38.2 ##STR00181## 1H-indazole-5-sulfonic acid (3-
methylphenyl)isobutylamide (310 mg; 27%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 344
Intermediate 39.2 ##STR00182## 1H-indazole-5-sulfonic acid (3-
methoxyphenyl)isobutylamide (450 mg; 62%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 360
Intermediate 40.2 ##STR00183## 1H-indazole-5-sulfonic acid (4-
trifluoromethoxyphenyl)isobutylamide (100 mg; 55%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
414 Intermediate 42.2 ##STR00184## 1H-indazole-5-sulfonic acid (3-
methoxypyridin-2-yl)isobutylamide (300 mg; 37%) obtained in the
form of a colorless oil with a compliant .sup.1H NMR. MS: [M + H] =
361 Intermediate 43.2 ##STR00185## 1H-indazole-5-sulfonic acid (3-
chlorobenzyl)isobutylamide (50 mg; 30%) obtained in the form of a
colorless oil with a compliant .sup.1H NMR. MS: [M + H] = 378
Intermediate 44.2 ##STR00186## 1H-indazole-5-sulfonic acid
isobutyl(2- trifluoromethylbenzyl)amide (70 mg; 39%) obtained in
the form of a colorless oil with a compliant .sup.1H NMR. MS: [M +
H] = 412 Intermediate 45.2 ##STR00187## 1H-indazole-5-sulfonic acid
(2- fluoro-6-methylphenyl)isobutylamide (305 mg; 65%) obtained in
the form of a white solid with a compliant .sup.1H NMR. MS: [M + H]
= 362 Intermediate 46.2 ##STR00188## 1H-indazole-5-sulfonic acid
(4- fluoro-2-methylphenyl)isobutylamide (307 mg; 65%) is obtained
in the form of a yellowish solid with a compliant .sup.1H NMR. MS:
[M - H] = 360 Intermediate 47.2 ##STR00189## 1H-indazole-5-sulfonic
acid isobutyl(4-methoxy-2- methylphenyl)amide (437 mg; 89%)
obtained in the form of a colorless oil with a compliant .sup.1H
NMR. MS: [M + H] = 374 Intermediate 48.1 ##STR00190## methyl
4-(1H-indazole-5- sulfonylamino)-3-methylbenzoate Obtained from the
commercial amine. (480 mg; 63%) obtained in the form of a white
solid with a compliant .sup.1H NMR. MS: [M - H] = 346 Intermediate
49.1 ##STR00191## 1H-indazole-5-sulfonic acid (4-
cyano-2-methylphenyl)amide Obtained from the commercial amine. (330
mg; 80%) obtained in the form of a beige-colored solid with a
compliant .sup.1H NMR. MS: [M - H] = 313
1. Synthesis of Intermediate 24.2
##STR00192##
1H-indazole-5-sulfonic acid
(4-ethylphenyl)(2,2,2-trifluoroethyl)amide
A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol),
pyridine (3 ml), potassium iodide (7.3 mg; 0.04 mmol),
4-dimethylaminopyridine (5.4 mg; 0.04 mmol) and
N-(4-ethylphenyl)-N-(2,2,2-trifluoroethyl)amine hydrochloride (231
mg; 0.96 mmol) is stirred for 16 hours at a temperature of
100.degree. C.
Silver(I) fluoride (5.6 mg; 0.04 mmol) is added to the reaction
medium, which is stirred for 3 days at a temperature of 80.degree.
C.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1H-indazole-5-sulfonic acid
(4-ethylphenyl)(2,2,2-trifluoroethyl)amide (20 mg; 6%) is obtained
in the form of a clear yellow oil.
MS: [M+H]=384
2. Synthesis of Intermediate 30.2
##STR00193##
1H-indazole-5-sulfonic acid (2-chlorophenyl)isobutylamide
A mixture of 1H-indazole-5-sulfonyl chloride (200 mg; 0.88 mmol),
pyridine (3.0 ml), potassium iodide (14 mg; 0.08 mmol),
4-dimethylaminopyridine (5.4 mg; 0.04 mmol) and
(2-chlorophenyl)isobutylamine (600 mg; 3.27 mmol) is stirred for 3
days at a temperature of 100.degree. C.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1H-indazole-5-sulfonic acid (2-chlorophenyl)isobutylamide (10 mg;
3%) is obtained in the form of a yellow oil with a compliant
.sup.1H NMR.
MS: [M+H]=364
3. Synthesis of Intermediate 41.2
##STR00194##
1H-indazole-5-sulfonic acid
cyclopropylmethyl(4-ethylphenyl)amide
With the same procedure as that used for intermediate 30.2,
1H-indazole-5-sulfonic acid cyclopropylmethyl(4-ethylphenyl)amide
(40 mg; 12%) is obtained in the form of a yellow oil with a
compliant .sup.1H NMR.
MS: [M+H]=373
4. Synthesis of Intermediate 45.2
##STR00195##
1H-indazole-5-sulfonic acid
(2-fluoro-6-methylphenyl)isobutylamide
(2-Fluoro-6-methylphenyl)isobutylamine (520 mg; 2.87 mmol) is added
to a solution of 1H-indazole-5-sulfonyl chloride (297.4 mg; 1.30
mmol) in acetonitrile (1.25 ml) and the reaction medium is stirred
for 40 minutes with microwave irradiation at a temperature of
100.degree. C. The reaction medium is treated with 1N hydrochloric
acid solution and extracted with ethyl acetate. The organic phases
are combined, washed with water, dried (MgSO.sub.4), filtered and
concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 60% of ethyl acetate). The
1H-indazole-5-sulfonic acid (2-fluoro-6-methylphenyl)isobutylamide
(305 mg; 65%) is obtained in the form of a white solid with a
compliant .sup.1H NMR.
MS: [M+H]=362
With a procedure similar to that described for the synthesis of
example 1, the addition of 1.2 equivalents of
4-(bromomethyl)tetrahydropyran to 1 equivalent of N-substituted
1H-indazole-5-sulfonamide (prepared previously) in
N,N-dimethylformamide in the presence of 1 equivalent of cesium
carbonate under microwave irradiation at 100.degree. C. leads to
the compounds in the table below:
TABLE-US-00007 Example 12 ##STR00196## N-(cyclopropylmethyl)-N-(4-
ethylphenyl)-1-((tetrahydro-2H-pyran-
4-yl)methyl)-1H-indazole-5-sulfonamide .sup.1H NMR (DMSO-d6)
.delta.: 0.23-0.35 (m, 2H), 0.64-0.77 (m, 1H), 1.12 (t, J = 7.6 Hz,
3H), 1.19-1.37 (m, 4H), 2.10 (dtd, J = 11.1, 6.9, 3.4 Hz, 1H), 2.54
(q, J = 7.6 Hz, 2H), 3.17 (td, J = 11.3, 3.0 Hz, 2H), 3.38 (d, J =
7.0 Hz, 2H), 3.76 (ddd, J = 11.5, 4.4, 2.2 Hz, 2H), 4.32 (d, J =
7.1 Hz, 2H), 6.89-6.97 (m, 2H), 7.11 (d, J = 8.3 Hz, 2H), 7.45 (dd,
J = 8.9, 1.7 Hz, 1H), 7.85 (dt, J = 8.8, 0.9 Hz, 1H), 8.06 (d, J =
1.6 Hz, 1H), 8.23 (d, J = 0.9 Hz, 1H). MS: [M + H] = 454 Example 13
##STR00197## N-(cyclobutylmethyl)-N-(4-
ethylphenyl)-1-((tetrahydro-2H-pyran-
4-yl)methyl)-1H-indazole-5-sulfonamide .sup.1H NMR (DMSO-d6)
.delta.: 1.17 (t, J = 7.6 Hz, 3H), 1.24-1.45 (m, 4H), 1.54-1.66 (m,
2H), 1.69-1.89 (m, 4H), 2.10-2.30 (m, 2H), 2.59 (q, J = 7.6 Hz,
2H), 3.27 (td, J = 11.6, 2.4 Hz, 2H), 3.56 (d, J = 7.5 Hz, 2H),
3.83 (ddd, 2H), 4.40 (d, J = 7.1 Hz, 2H), 6.88-6.96 (m, 2H), 7.15
(d, J = 8.3 Hz, 2H), 7.31 (dd, J = 9.1, 1.8 Hz, 1H), 7.75 (d, J =
9.1 Hz, 1H), 8.12-8.14 (m, 1H), 8.63 (d, J = 0.9 Hz, 1H) MS: [M +
H] = 468 Example 14 ##STR00198## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid cyclopentyl(4- ethylphenyl)amide .sup.1H
NMR (DMSO-d6) .delta.: 1.12-1.26 (m, 5H), 1.26-1.49 (m, 9H), 1.74
(dd, J = 12.2, 6.9 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 3.24 (td, J =
11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.2 Hz, 2H), 4.39 (d,
J = 7.0 Hz, 2H), 4.46-4.57 (m, 1H), 6.87- 6.92 (m, 2H), 7.17-7.23
(m, 2H), 7.69 (dd, J = 9.0, 1.8 Hz, 1H), 7.91-7.96 (m, 1H), 8.21
(d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H) MS: [M + H] = 468
Example 15 ##STR00199## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid cyclobutyl(4- ethylphenyl)amide .sup.1H
NMR (DMSO-d6) .delta.: 1.18 (t, J = 7.6 Hz, 3H), 1.23-1.62 (m, 6H),
1.76 (dq, J = 12.0, 9.7 Hz, 2H), 2.05 (dddd, J = 9.4, 7.4, 5.1, 2.5
Hz, 2H), 2.10-2.26 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.24 (td, J =
11.3, 2.9 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.1 Hz, 2H), 4.38 (dd,
J = 8.5, 6.5 Hz, 3H), 6.80 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3
Hz, 2H), 7.48 (dd, J = 9.0, 1.8 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H),
8.11 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H) MS: [M + H] = 454 Example 16
##STR00200## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (4- ethylphenyl)(tetrahydrofuran-3- ylmethyl)amide .sup.1H NMR
(DMSO-d6) .delta.: 1.18 (t, J = 7.6 Hz, 3H), 1.25-1.43 (m, 4H),
1.58 (dq, J = 13.2, 6.8 Hz, 1H), 1.76-1.90 (m, 1H), 2.06 (p, J =
5.9 Hz, 1H), 2.11-2.22 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.24 (td,
J = 11.3, 3.0 Hz, 2H), 3.42 (dd, J = 8.6, 5.2 Hz, 1H), 3.48-3.62
(m, 4H), 3.71 (td, J = 8.1, 5.4 Hz, 1H), 3.76-3.89 (m, 2H), 4.39
(d, J = 7.0 Hz, 2H), 6.91-7.00 (m, 2H), 7.14 -7.24 (m, 2H), 7.48
(dd, J = 9.0, 1.7 Hz, 1H), 7.87-7.95 (m, 1H), 8.12 (d, J = 1.6 Hz,
1H), 8.30 (d, J = 1.0 Hz, 1H) MS: [M + H] = 484 Example 17
##STR00201## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid sec-butyl(4- ethylphenyl)amide .sup.1H NMR (DMSO-d6) .delta.:
0.85 (t, J = 7.3 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 1.12- 1.25 (m,
5H), 1.26-1.44 (m, 4H), 2.62 (q, J = 7.6 Hz, 2H), 3.24 (td, J =
11.3, 3.2 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.3 Hz, 2H), 4.19 (dt,
J = 7.8, 6.4 Hz, 1H), 4.39 (d, J = 7.1 Hz, 2H), 6.91 (d, J = 8.3
Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.68 (dd, J = 8.9, 1.8 Hz, 1H),
7.94 (dt, J = 9.0, 0.9 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.30 (d,
J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 18 ##STR00202##
N-(4-ethylphenyl)-N-isopentyl-1-
((tetrahydro-2H-pyran-4-yl)methyl)- 1H-indazole-5-sulfonamide
.sup.1H NMR (DMSO-d6) .delta.: 0.80 (d, J = 6.6 Hz, 6H), 1.17 (t, J
= 7.6 Hz, 5H), 1.25- 1.42 (m, 4H), 1.61 (hept, J = 6.7 Hz, 1H),
2.09-2.24 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.23 (td, J = 11.2,
3.1 Hz, 2H), 3.55 (t, J = 7.1 Hz, 2H), 3.81 (dt, J = 11.5, 3.3 Hz,
2H), 4.38 (d, J = 7.1 Hz, 2H), 6.90- 6.99 (m, 2H), 7.12-7.22 (m,
2H), 7.47 (dd, J = 9.0, 1.7 Hz, 1H), 7.87-7.96 (m, 1H), 8.11 (d, J
= 2.0 Hz, 1H), 8.30 (d, J = 1.1 Hz, 1H) MS: [M + H] = 470 Example
19 ##STR00203## N-(4-ethylphenyl)-N-isopropyl-1-
((tetrahydro-2H-pyran-4-yl)methyl)- 1H-indazole-5-sulfonamide
.sup.1H NMR (DMSO-d6) .delta.: 0.95 (d, J = 6.7 Hz, 6H), 1.19 (t, J
= 7.6 Hz, 3H), 1.26- 1.45 (m, 4H), 2.63 (q, J = 7.6 Hz, 2H), 3.24
(td, J = 11.3, 3.0 Hz, 2H), 3.82 (ddd, J = 11.5, 4.3, 2.2 Hz, 2H),
4.39 (d, J = 7.1 Hz, 2H), 4.47 (p, J = 6.7 Hz, 1H), 6.90- 6.98 (m,
2H), 7.22 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 8.9, 1.8 Hz, 1H),
7.90-7.99 (m, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9 Hz,
1H). MS: [M + H] = 442 Example 20 ##STR00204##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
ethylphenyl)(1-ethylpropyl)amide .sup.1H NMR (DMSO-d6) .delta.:
0.85 (t, J = 7.3 Hz, 6H), 1.07-1.22 (m, 5H), 1.30 (ddd, J = 20.0,
9.0, 5.7 Hz, 6H), 2.16 (s, 1H), 2.61 (q, J = 7.6 Hz, 2H), 3.23 (td,
J = 11.2, 3.4 Hz, 2H), 3.81 (d, J = 11.1 Hz, 2H), 3.91 (q, J = 6.5
Hz, 1H), 4.39 (d, J = 7.2 Hz, 2H), 6.86-6.93 (m, 2H), 7.21 (d, J =
8.3 Hz, 2H), 7.93 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H),
8.29 (d, J = 0.9 Hz, 1H). MS: [M + H] = 470 Example 22 ##STR00205##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
ethylphenyl)propylamide .sup.1H NMR (DMSO-d6) .delta.: 0.83 (t, J =
7.3 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H), 1.25- 1.44 (m, 6H), 2.24
(ddt, J = 10.9, 7.5, 3.8 Hz, 1H), 2.60 (q, J = 7.5 Hz, 2H), 3.26
(td, J = 11.6, 2.5 Hz, 2H), 3.50 (t, J = 6.9 Hz, 2H), 3.83 (ddd, J
= 11.5, 4.5, 2.0 Hz, 2H), 4.40 (d, J = 7.1 Hz, 2H), 6.93-7.02 (m,
2H), 7.17 (d, J = 8.3 Hz, 2H), 7.29 (dd, J = 9.1, 1.8 Hz, 1H),
7.70-7.80 (m, 1H), 8.12 (dd, J = 1.9, 0.8 Hz, 1H), 8.62 (d, J =
11.0 Hz, 1H) MS: [M + H] = 442 Example 23 ##STR00206##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
butyl(4- ethylphenyl)amide .sup.1H NMR (DMSO-d6) .delta.: 0.74-0.88
(m, 3H), 1.17 (t, J = 7.6 Hz, 3H), 1.23-1.45 (m, 8H), 2.24 (ddt, J
= 11.0, 7.6, 3.8 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 3.26 (td, J =
11.5, 2.5 Hz, 2H), 3.54 (q, J = 4.4 Hz, 2H), 3.83 (ddd, J = 11.5,
4.3, 2.0 Hz, 2H), 4.40 (d, J = 7.2 Hz, 2H), 6.93-7.01 (m, 2H), 7.17
(d, J = 8.3 Hz, 2H), 7.28 (dd, J = 9.1, 1.8 Hz, 1H), 7.74 (dd, J =
9.0, 1.0 Hz, 1H), 8.11-8.14 (m, 1H), 8.62 (d, J = 0.9 Hz, 1H). MS:
[M + H] = 456 Example 25 ##STR00207##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
butyl(4- isopropylphenyl)amide .sup.1H NMR (DMSO-d6) .delta.: 0.85
(d, J = 6.7 Hz, 6H), 1.19 (d, J = 6.9 Hz, 6H), 1.25- 1.50 (m, 5H),
2.11-2.22 (m, 1H), 2.88 (hept, J = 6.8 Hz, 1H), 3.23 (td, J = 11.3,
2.9 Hz, 2H), 3.82 (ddd, J = 11.6, 4.4, 2.2 Hz, 2H), 4.38 (d, J =
7.1 Hz, 2H), 6.94- 7.03 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.44
(dd, J = 8.9, 1.8 Hz, 1H), 7.85-7.94 (m, 1H), 8.09 (d, J = 1.7 Hz,
1H), 8.29 (d, J = 0.9 Hz, 1H) MS: [M + H] = 470 Example 26
##STR00208## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (5-chloro-2- fluorophenyl)isobutylamide .sup.1H NMR (DMSO-d6)
.delta.: 0.85 (d, J = 6.6 6H), 1.21-1.49 (m, 5H), 2.17 (dd, J =
10.5, 5.9 Hz, 1H), 3.23 (td, J = 11.1, 3.3 Hz, 2H), 3.76-3.87 (m,
2H), 4.40 (d, J = 7.0 Hz, 2H), 7.15 (dd, J = 6.5, 2.7 Hz, 1H), 7.35
(dd, J = 10.1, 8.9 Hz, 1H), 7.50 (ddd, J = 8.8, 4.1, 2.6 Hz, 1H),
7.56 (dd, J = 9.0, 1.8 Hz, 1H), 7.92-7.99 (m, 1H), 8.20 (d, J = 1.7
Hz, 1H), 8.33 (d, J = 1.0 Hz, 1H). MS: [M + H] = 480 Example 27
##STR00209## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (5-fluoro-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6)
.delta.: 0.77 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.22-
1.49 (m, 5H), 2.07-2.25 (m, 1H), 2.27 (s, 3H), 3.13 (dd, J = 13.2,
4.7 Hz, 1H), 3.23 (td, J = 11.2, 3.4 Hz, 2H), 3.43 (dd, J = 13.2,
9.1 Hz, 1H), 3.81 (dt, J = 11.5, 3.2 Hz, 2H), 4.40 (d, J = 7.1 Hz,
2H), 6.45 (dd, J = 10.1, 2.7 Hz, 1H), 7.12 (td, J = 8.3, 2.7 Hz,
1H), 7.35 (dd, J = 8.6, 6.6 Hz, 1H), 7.51 (dd, J = 8.9, 1.8 Hz,
1H), 7.91- 7.99 (m, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 0.9
Hz, 1H). MS: [M + H] = 460 Example 28 ##STR00210##
1-(tetrahydropyran-4-ylmethyl)-2H- indazole-5-sulfonic acid
(3-fluoro-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6)
.delta.: 0.77 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H), 1.18-
1.52 (m, 5H), 2.08-2.27 (m, 4H), 3.13 (dd, J = 13.1, 4.8 Hz, 1H),
3.23 (td, J = 11.2, 3.1 Hz, 2H), 3.46 (dd, J = 13.2, 9.0 Hz, 1H),
3.73-3.88 (m, 2H), 4.39 (d, J = 7.1 Hz, 2H), 6.52 (d, J = 8.1 Hz,
1H), 7.06- 7.26 (m, 2H), 7.52 (dd, J = 8.9, 1.8 Hz, 1H), 7.93 (d, J
= 8.8 Hz, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 1.0 Hz, 1H).
MS: [M + H] = 460 Example 29 ##STR00211##
1-tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (5-
chlorophenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.: 0.85 (d,
J = 6.6 Hz, 6H), 1.21-1.50 (m, 5H), 3.23 (td, J = 11.2, 3.2 Hz,
2H), 3.38 (d, J = 7.3 Hz, 2H), 3.80 (s, 2H), 4.38 (d, J = 7.1 Hz,
2H), 7.08 (dt, J = 7.0, 2.0 Hz, 1H), 7.13 (t, J = 1.9 Hz, 1H),
7.34-7.40 (m, 2H), 7.41- 7.44 (m, 1H), 7.91 (d, J = 8.9 Hz, 1H),
8.11 (d, J = 1.7 Hz, 1H), 8.31 (d, J = 1.0 Hz, 1H). MS: [M + H] =
462 Example 30 ##STR00212## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid (2- chlorophenyl)isobutylamide .sup.1H NMR
(400 MHz, CDCl3) .delta. 0.86 (t, J = 6.2 Hz, 6H), 1.37 (td, J =
10.9, 9.9, 4.0 Hz, 4H), 1.55 (dt, J = 13.5, 6.8 Hz, 2H), 2.22 (s,
1H), 3.28 (td, J = 11.1, 4.0 Hz, 2H), 3.36 (dd, J = 7.2, 1.8 Hz,
2H), 3.89 (dt, J = 11.6, 3.3 Hz, 2H), 4.22 (d, J = 7.1 Hz, 2H),
7.19 (m, 3H), 7.25-7.30 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.61
(dd, J = 8.9, 1.7 Hz, 1H), 8.03 (s, 1H), 8.07 (d, J = 1.6 Hz, 1H).
MS: [M + H] = 462 Example 31 ##STR00213##
1-(tetrahydrouyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
fluorophenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.: 0.85 (d,
J = 6.6 Hz, 6H), 1.23-1.48 (m, 5H), 2.16 (ddd, J = 11.0, 6.9, 4.2
Hz, 1H), 3.23 (td, J = 11.3, 2.9 Hz, 2H), 3.35 (s, 2H), 3.82 (ddd,
J = 11.5, 4.5, 2.2 Hz, 2H), 4.38 (d, J = 7.0 Hz, 2H), 7.05-7.22 (m,
4H), 7.45 (dd, J = 8.9, 1.7 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 8.07
(d, J = 1.7 Hz, 1H), 8.30 (s, 1H). MS: [M + H] = 446 Example 32
##STR00214## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid isobutyl-p- tolylamide .sup.1H NMR (DMSO-d6) .delta.: 0.85 (d,
J = 6.7 Hz, 6H), 1.23-1.48 (m, 5H), 2.05-2.25 (m, 1H), 2.29 (s,
3H), 3.24 (td, J = 11.3, 2.8 Hz, 3H), 3.32 (td, 2H), 3.82 (dd, J =
11.3, 3.7 Hz, 2H), 4.38 (d, J = 7.1 Hz, 2H), 6.89-6.95 (m, 2H),
7.13 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 8.9, 1.8 Hz, 1H), 7.89 (d,
J = 8.8 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H). MS: [M +
H] = 442 Example 33 ##STR00215## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid isobutyl-o- tolylamide .sup.1H NMR
(DMSO-d6) .delta.: 0.76 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.6 Hz,
3H), 1.24- 1.50 (m, 5H), 2.07-2.26 (m, 1H), 2.30 (s, 3H), 3.13 (dd,
J = 13.2, 4.9 Hz, 1H), 3.24 (td, J = 11.0, 2.9 Hz, 2H), 3.45 (dd, J
= 13.1, 8.9 Hz, 1H), 3.82 (dd, J = 13.4, 2.4 Hz, 2H), 4.40 (d, J =
7.1 Hz, 2H), 6.62 (dd, J = 8.1, 1.3 Hz, 1H), 7.08 (td, J = 7.7, 1.7
Hz, 1H), 7.24 (td, J = 7.5, 1.3 Hz, 1H), 7.31 (dd, J = 7.8, 1.6 Hz,
1H), 7.53 (dd, J = 8.9, 1.8 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 8.13
(s, 1H), 8.32 (s, 1H). MS: [M + H] = 442 Example 34 ##STR00216##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,5-
dimethylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.: 0.77
(d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.26- 1.38 (m, 4H),
1.44 (dtd, J = 8.9, 6.7, 4.8 Hz, 1H), 2.03 (s, 3H), 2.12-2.22 (m,
1H), 2.23 (s, 3H), 3.07 (dd, J = 13.1, 4.8 Hz, 1H), 3.19-3.27 (m,
2H), 3.43 (dd, J = 13.1, 8.9 Hz, 1H), 3.81 (dq, J = 10.8, 3.4 Hz,
2H), 4.41 (d, J = 7.0 Hz, 2H), 6.29 (d, J = 1.7 Hz, 1H), 7.04 (dd,
J = 7.8, 1.8 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.49 (dd, J = 9.0,
1.7 Hz, 1H), 7.93 (dt, J = 9.0, 0.9 Hz, 1H), 8.13 (d, J = 1.6 Hz,
1H), 8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 456 Example 35
##STR00217## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (4-butyl-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6)
.delta.: 0.75 (d, J = 6.6 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H), 0.95
(d, J = 6.6 Hz, 3H), 1.24-1.47 (m, 8H), 1.48- 1.59 (m, 2H), 2.16
(s, 1H), 2.25 (s, 3H), 3.09 (dd, J = 13.1, 4.9 Hz, 1H), 3.24 (td, J
= 11.1, 3.2 Hz, 2H), 3.37-3.46 (m, 1H), 3.77-3.88 (m, 2H), 4.39 (d,
J = 7.0 Hz, 2H), 6.52 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.2, 2.2
Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 9.0, 1.7 Hz, 1H),
7.85- 7.98 (m, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz,
1H) MS: [M + H] = 498 Example 36 ##STR00218##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (2,4-
dimethylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.: 0.76
(d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H), 1.22- 1.48 (m, 5H),
2.09 (d, J = 4.8 Hz, 1H), 2.11-2.21 (m, 1H), 2.25 (d, J = 4.1 Hz,
6H), 3.08 (dd, J = 13.1, 4.8 Hz, 1H), 3.24 (td, J = 11.2, 3.2 Hz,
2H), 3.43 (dd, J = 13.1, 8.9 Hz, 1H), 3.76-3.87 (m, 2H), 4.40 (d, J
= 7.0 Hz, 2H), 6.48 (d, J = 8.1 Hz, 1H), 6.87 (dd, J = 8.1, 2.1 Hz,
1H), 7.11 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 9.0, 1.7 Hz, 1H),
7.90-7.96 (m, 1H), 8.13 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 0.9 Hz,
1H) MS: [M + H] = 456 Example 37 ##STR00219##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3,5-
dimethylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.: 0.85
(d, J = 6.6 Hz, 6H), 1.22-1.38 (m, 4H), 1.44 (hept, J = 6.8 Hz,
1H), 2.16 (s, 7H), 3.23 (td, J = 11.1, 3.6 Hz, 2H), 3.29 (d, J =
7.3 Hz, 2H), 3.76-3.85 (m, 2H), 4.39 (d, J = 7.0 Hz, 2H), 6.58-6.63
(m, 2H), 6.94 (s, 1H), 7.42 (dd, J = 8.8, 1.7 Hz, 1H), 7.87- 7.92
(m, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz, 1H) MS: [M
+ H] = 456 Example 38 ##STR00220##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-
methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.: 0.85 (d,
J = 6.6 Hz, 6H), 1.23-1.52 (m, 5H), 2.22 (s, 4H), 3.23 (td, J =
11.3, 3.2 Hz, 2H), 3.77- 3.87 (m, 2H), 4.38 (d, J = 7.1 Hz, 2H),
6.78-6.89 (m, 2H), 7.10-7.15 (m, 1H), 7.20 (t, J = 7.7 Hz, 1H),
7.85-7.93 (m, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.9
Hz,
1H) MS: [M + H] = 442 Example 39 ##STR00221##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (3-
methoxyphenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.: 0.86 (d,
J = 6.6 Hz, 6H), 1.21-1.38 (m, 4H), 1.45 (hept, J = 6.8 Hz, 1H),
3.23 (td, J = 11.3, 3.2 Hz, 2H), 3.61 (s, 3H), 3.81 (dt, J = 11.7,
2.7 Hz, 2H), 4.38 (d, J = 7.0 Hz, 2H), 6.53 (t, J = 2.3 Hz, 1H),
6.66 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 6.89 (ddd, J = 8.3, 2.5, 0.9
Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.9, 1.7 Hz, 1H),
7.88-7.94 (m, 1H), 8.10 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 0.8 Hz,
1H) MS: [M + H] = 458 Example 40 ##STR00222##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid (4-
trifluoromethoxyphenyl)isobutylamide .sup.1H NMR (DMSO-d6) .delta.:
0.85 (d, J = 6.6 Hz, 6H), 1.24-1.47 (m, 5H), 2.10-2.20 (m, 1H),
3.23 (td, J = 11.3, 2.9 Hz, 2H), 3.37 (d, J = 7.4 Hz, 2H), 3.80 (s,
2H), 4.38 (d, J = 7.1 Hz, 2H), 7.20-7.26 (m, 2H), 7.32-7.37 (m,
2H), 7.43 (dd, J = 9.0, 1.8 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 8.10
(d, J = 1.7 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H); MS: [M + H] = 512
Example 41 ##STR00223## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid isobutyl(5- isopropylpyridin-2-yl)amide
.sup.1H NMR (Chloroform-d) .delta.: 0.82 (d, J = 6.7 Hz, 6H), 1.20
(s, 6H), 1.30-1.44 (m, 4H), 2.15-2.28 (m, 1H), 2.87 (p, J = 7.0 Hz,
1H), 3.28 (td, J = 11.5, 3.0 Hz, 2H), 3.42 (d, J = 7.3 Hz, 2H),
3.86-3.93 (m, 2H), 4.18 (d, J = 7.2 Hz, 2H), 7.29-7.33 (m, 1H),
7.40 (dd, J = 9.0, 1.7 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.55 (dd,
J = 8.3, 2.5 Hz, 1H), 8.01 (d, J = 0.8 Hz, 1H), 8.04 (d, J = 1.8
Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H). MS: [M + H] = 471 Example 42
##STR00224## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid (3- methoxypyridin-2-yl)isobutylamide .sup.1H NMR (DMSO-d6)
.delta.: 0.86 (d, J = 6.6 Hz, 6H), 1.20-1.37 (m, 4H), 1.57 (hept, J
= 6.9 Hz, 1H), 2.03-2.24 (m, 1H), 3.12- 3.26 (m, 3H), 3.42 (s, 3H),
3.53 (d, J = 7.1 Hz, 2H), 3.71-3.87 (m, 2H), 4.37 (d, J = 7.1 Hz,
2H), 6.69 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.46 (dd,
J = 9.0, 1.8 Hz, 1H), 7.73-7.82 (m, 1H), 7.88 (dd, J = 9.0, 1.0 Hz,
1H), 8.19 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H) MS: [M + H]
= 459 Example 43 ##STR00225## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid (3- chlorobenzyl)isobutylamide .sup.1H NMR
(DMSO-d6) .delta.: 0.70 (d, J = 6.6 Hz, 6H), 1.25-1.42 (m, 4H),
1.58 (dt, J = 13.6, 6.9 Hz, 1H), 2.92 (d, J = 7.6 Hz, 2H), 3.24
(td, J = 11.3, 3.2 Hz, 2H), 3.82 (d, J = 11.2 Hz, 2H), 4.33 (s,
2H), 4.40 (d, J = 7.1 Hz, 2H), 7.24-7.37 (m, 4H), 7.80 (dd, J =
9.0, 1.7 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 8.31 (d, J = 0.9 Hz,
1H), 8.37 (d, J = 1.7 Hz, 1H) MS: [M + H] = 476 Example 44
##STR00226## 1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic
acid isobutyl(2- trifluoromethylbenzyl)amide .sup.1H NMR (DMSO-d6)
.delta.: 0.70 (d, J = 6.6 Hz, 6H), 1.23-1.43 (m, 5H), 2.97 (d, J =
7.2 Hz, 2H), 3.24 (td, J = 11.3, 3.0 Hz, 2H), 3.82 (d, J = 10.7 Hz,
2H), 4.40 (d, J = 7.1 Hz, 2H), 4.48 (s, 2H), 7.50 (t, J = 7.6 Hz,
1H), 7.70 (q, J = 7.6 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.83 (dd,
J = 8.9, 1.8 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 8.39 (d, J = 1.7
Hz, 1H) MS: [M + H] = 510 Example 45 ##STR00227##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(2-fluoro-6- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6)
.delta.: 0.77 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.21-
1.39 (m, 4H), 1.41-1.57 (m, 1H), 2.08- 2.25 (m, 1H), 2.28 (s, 3H),
3.15 (dd, J = 13.7, 5.8 Hz, 1H), 3.23 (td, J = 11.0, 3.7 Hz, 2H),
3.45 (dd, J = 13.6, 7.9 Hz, 1H), 3.81 (dt, J = 11.4, 3.3 Hz, 2H),
4.39 (d, J = 7.0 Hz, 2H), 7.00 (ddd, J = 10.2, 8.3, 1.6 Hz, 1H),
7.15 (d, J = 7.6 Hz, 1H), 7.23- 7.36 (m, 1H), 7.63 (dd, J = 8.9,
1.8 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H),
8.31 (d, J = 1.0 Hz, 1H) MS: [M + H] = 460 Example 46 ##STR00228##
1-(tetrahyropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
(4-fluoro-2- methylphenyl)isobutylamide .sup.1H NMR (DMSO-d6)
.delta.: 0.77 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.24-
1.50 (m, 5H), 2.11-2.24 (m, 1H), 2.29 (s, 3H), 3.10 (dd, J = 13.1,
4.8 Hz, 1H), 3.23 (td, J = 11.2, 3.2 Hz, 2H), 3.45 (dd, J = 13.2,
8.9 Hz, 1H), 3.82 (dt, J = 11.6, 2.7 Hz, 2H), 4.39 (d, J = 7.1 Hz,
2H), 6.66 (dd, J = 8.9, 5.5 Hz, 1H), 6.92 (td, J = 8.4, 3.1 Hz,
1H), 7.18 (dd, J = 9.8, 3.0 Hz, 1H), 7.53 (dd, J = 8.9, 1.7 Hz,
1H), 7.93 (dd, J = 9.0, 0.9 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.32
(d, J = 0.9 Hz, 1H) MS: [M + H] = 460 Example 47 ##STR00229##
1-(tetrahydropyran-4-ylmethyl)-1H- indazole-5-sulfonic acid
isobutyl(4- methoxy-2-methylphenyl)amide 1H NMR (DMSO-d6) .delta.:
0.76 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.23- 1.53 (m,
5H), 2.08-2.21 (m, 1H), 2.24 (s, 3H), 3.07 (dd, J = 13.0, 4.8 Hz,
1H), 3.24 (td, J = 11.2, 3.2 Hz, 2H), 3.43 (dd, J = 13.1, 8.9 Hz,
1H), 3.73 (s, 3H), 3.82 (dt, J = 11.4, 3.3 Hz, 2H), 4.39 (d, J =
7.1 Hz, 2H), 6.51 (d, J = 8.8 Hz, 1H), 6.61 (dd, J = 8.8, 3.0 Hz,
1H), 6.85 (d, J = 2.9 Hz, 1H), 7.53 (dd, J = 8.9, 1.7 Hz, 1H),
7.87- 7.96 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 0.9 Hz,
1H) MS: [M + H] = 472 Example 48 ##STR00230## methyl
4-{isobutyl[1-(tetrahydropyran- 4-ylmethyl)-1H-indazole-5-
sulfonyl]amino}-3-methylbenzoate .sup.1H NMR (DMSO-d6) .delta.:
0.76 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.23- 1.49 (m,
5H), 2.09-2.23 (m, 1H), 2.37 (s, 3H), 3.15 (dd, J = 13.2, 4.8 Hz,
1H), 3.24 (td, J = 11.2, 3.0 Hz, 2H), 3.46 (dd, J = 13.3, 8.9 Hz,
1H), 3.75-3.88 (m, 5H), 4.40 (d, J = 7.1 Hz, 2H), 6.80 (d, J = 8.3
Hz, 1H), 7.51 (dd, J = 8.9, 1.7 Hz, 1H), 7.65 (dd, J = 8.3, 2.2 Hz,
1H), 7.91 (d, J = 2.2 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 8.15 (d, J
= 1.7 Hz, 1H), 8.32 (d, J = 0.9 Hz, 1H) MS: [M + H] = 500 Example
49 ##STR00231## 1-(tetrahydropyran-4-ylmethyl)-1H-
indazole-5-sulfonic acid (4-cyano-2- methylphenyl)isobutylamide
.sup.1H NMR (DMSO-d6) .delta.: 0.76 (d, J = 6.6 Hz, 3H), 0.93 (d, J
= 6.5 Hz, 3H), 1.21- 1.48 (m, 5H), 2.06-2.25 (m, 1H), 2.35 (s, 3H),
3.07-3.29 (m, 3H), 3.45 (dd, J = 13.3, 9.0 Hz, 1H), 3.82 (dd, J =
10.1, 3.2 Hz, 2H), 4.40 (d, J = 7.0 Hz, 2H), 6.88 (d, J = 8.3 Hz,
1H), 7.52 (dd, J = 9.0, 1.8 Hz, 1H), 7.59 (dd, J = 8.2, 2.1 Hz,
1H), 7.86 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 9.0, 0.9 Hz, 1H), 8.15
(d, J = 1.6 Hz, 1H), 8.33 (d, J = 1.0 Hz, 1H). MS: [M + H] =
467
Example 50: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)(tetrahydropyran-4-ylmethyl)amide
##STR00232##
1. Synthesis of Intermediate 50.1
##STR00233##
1H-indazole-5-sulfonic acid (4-ethylphenyl)amide
A mixture of 1H-indazole-5-sulfonyl chloride (1.00 g; 4.39 mmol),
pyridine (5.0 ml) and 4-ethylaniline (603 .mu.l; 4.82 mmol) is
stirred for 4 hours at 50.degree. C. The reaction medium is diluted
with ethyl acetate and extracted. The organic phase is washed with
saturated ammonium chloride solution, with saturated sodium
hydrogen carbonate solution and with water. It is dried
(MgSO.sub.4), filtered and concentrated to dryness.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The
1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.32 g; 100%) is
obtained in the form of an orange oil with a compliant .sup.1H
NMR.
MS: [M+H]=302
2. Synthesis of Compound 5 According to the Invention
##STR00234##
A mixture of 1H-indazole-5-sulfonic acid (4-ethylphenyl)amide (1.30
g; 4.31 mmol), cesium carbonate (2.11 g; 6.47 mmol) and
4-(bromomethyl)tetrahydropyran (680 .mu.l; 5.18 mmol; 1.20 eq.) in
N-methyl-2-pyrrolidone (10 ml) is stirred for 16 hours at a
temperature of 50.degree. C. The reaction medium is diluted with
ethyl acetate (30 ml). The organic phase is washed with saturated
NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution
(20 ml) and with water (20 ml). The organic phase is dried
(MgSO.sub.4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)(tetrahydropyran-4-ylmethyl)amide (360 mg; 17%) is
obtained in the form of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 1.08-1.23 (m, 5H), 1.25-1.47 (m,
5H), 1.52-1.62 (m, 2H), 2.60 (q, J=7.5 Hz, 2H), 3.13 (td, J=11.6,
2.2 Hz, 2H), 3.23 (td, J=11.3, 3.0 Hz, 2H), 3.43 (d, J=7.2 Hz, 2H),
3.72-3.87 (m, 4H), 4.38 (d, J=7.1 Hz, 2H), 6.97 (d, J=8.4 Hz, 2H),
7.17 (d, J=8.4 Hz, 2H), 7.46 (dd, J=9.0, 1.7 Hz, 1H), 7.84-7.98 (m,
1H), 8.10 (d, J=1.7 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H)
MS: [M+H]=498 Another fraction is obtained corresponding to the
mixture below:
##STR00235##
Intermediate 51.1: Mixture of
N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulf-
onamide and
N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulf-
onamide.
The mixture of
N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulf-
onamide and
N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulf-
onamide (170.00 mg; 10%) is obtained in the form of a solid with a
compliant .sup.1H NMR.
MS: [M+H]=400
Example 51: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
cyclopropyl(4-ethylphenyl)amide
##STR00236##
A spatulaful of molecular sieves is added to a mixture of
N-(4-ethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-5-sulf-
onamide and
N-(4-ethylphenyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazole-5-sulf-
onamide (170 mg; 0.43 mmol), triethylamine (180 .mu.l; 1.28 mmol),
copper(II) acetate (232 mg; 1.28 mmol) and cyclopropylboronic acid
(220 mg; 2.55 mmol) in dichloromethane (3 ml).
The reaction medium is stirred for 16 hours at room temperature
under 1 atmosphere of oxygen and filtered through Celite, which is
rinsed with dichloromethane (50 ml) and with water (20 ml). The
organic phase is extracted, washed with a mixture (1/1) of aqueous
ammonia and saturated NH.sub.4Cl solution (2.times.50 ml) and then
with water (50 ml), dried (MgSO.sub.4), filtered and
concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
cyclopropyl(4-ethylphenyl)amide 002 (40 mg; 21%) is obtained in the
form of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.62 (t, J=3.2 Hz, 2H), 0.76 (dt,
J=7.1, 3.6 Hz, 2H), 1.14-1.22 (m, 4H), 1.23-1.42 (m, 4H), 2.16 (dd,
J=10.8, 5.1 Hz, 1H), 2.58-2.71 (m, 3H), 3.17-3.29 (m, 3H),
3.76-3.89 (m, 2H), 4.38 (d, J=7.1 Hz, 2H), 6.87-7.02 (m, 2H), 7.15
(d, J=8.4 Hz, 2H), 7.46 (dd, J=8.8, 1.7 Hz, 1H), 7.91 (d, J=8.9 Hz,
1H), 8.15 (d, J=1.6 Hz, 1H), 8.33 (d, J=0.9 Hz, 1H)
MS: [M+H]=440
Example 52: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
isobutyl(2-trifluoromethylphenyl)amide
##STR00237##
1. Synthesis of Intermediate 52.1
##STR00238##
1H-indazole-5-sulfonic acid
(2-trifluoromethylphenyl)amide
A mixture of 1H-indazole-5-sulfonyl chloride (500.0 mg; 2.19 mmol),
pyridine (3.0 ml) and 2-(trifluoromethyl)aniline (306.18 .mu.l;
2.41 mmol) is stirred for 16 hours at a temperature of 40.degree.
C. The reaction medium is diluted with ethyl acetate and extracted.
The organic phase is washed with saturated ammonium chloride
solution, with saturated sodium hydrogen carbonate solution and
with water. It is dried (MgSO.sub.4), filtered and concentrated to
dryness.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 40% of ethyl acetate).
The 1H-indazole-5-sulfonic acid (2-trifluoromethylphenyl)amide (300
mg; 40%) is obtained in the form of a white solid with a compliant
.sup.1H NMR.
MS: [M+H]=342
2. Synthesis of Compound 58 According to the Invention
##STR00239##
Cesium carbonate (30 mg; 1.32 mmol) and
4-(bromomethyl)tetrahydropyran (127 .mu.l; 0.97 mmol) are added to
a solution of 1H-indazole-5-sulfonic acid
(2-trifluoromethylphenyl)amide (300 mg; 0.88 mmol) in
1-methyl-2-pyrrolidone (3 ml). The reaction medium is stirred for
16 hours at room temperature. 1-Bromo-2-methylpropane (287 .mu.l;
2.64 mmol) is added and the reaction medium is stirred for 6 hours
at 80.degree. C. The reaction medium is diluted with ethyl acetate,
washed with saturated ammonium chloride solution and then with
saturated sodium hydrogen carbonate solution and with water. The
organic phase is dried (MgSO.sub.4), filtered and concentrated to
dryness.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
isobutyl(2-trifluoromethylphenyl)amide (80 mg; 16%) is obtained in
the form of a beige-colored solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.71 (d, J=6.7 Hz, 3H), 0.85-0.93
(m, 3H), 1.25-1.43 (m, 4H), 1.48 (dtd, J=8.8, 6.6, 4.6 Hz, 1H),
2.12-2.25 (m, 1H), 3.15 (dd, J=13.4, 4.6 Hz, 1H), 3.24 (td, J=10.8,
10.4, 2.2 Hz, 2H), 3.46 (dd, J=13.4, 8.8 Hz, 1H), 3.78-3.86 (m,
2H), 4.41 (d, J=7.1 Hz, 2H), 6.99 (dd, J=5.7, 3.7 Hz, 1H), 7.56
(dd, J=9.0, 1.7 Hz, 1H), 7.58-7.64 (m, 2H), 7.85 (dt, J=5.6, 3.7
Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 8.18-8.24 (m, 1H), 8.35 (s,
1H).
MS: [M+H]=496
Example 53: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
isobutyl(4-trifluoromethylphenyl)amide
##STR00240##
1. Synthesis of Intermediate 53.1
##STR00241##
1H-indazole-5-sulfonic acid
(4-trifluoromethylphenyl)amide
A mixture of 1H-indazole-5-sulfonyl chloride (250.0 mg; 1.10 mmol)
and 4-(trifluoromethyl)aniline (388.6 .mu.l; 2.41 mmol) in
acetonitrile (1.7 ml) is stirred for 40 minutes at a temperature of
100.degree. C. under microwave irradiation. The reaction medium is
diluted with ethyl acetate and extracted.
The organic phase is washed with saturated ammonium chloride
solution, with saturated sodium hydrogen carbonate solution and
with water. It is dried (MgSO.sub.4), filtered and concentrated to
dryness.
The 1H-indazole-5-sulfonic acid (4-trifluoromethylphenyl)amide (297
mg; 79%) is obtained in the form of a yellowish solid with a
compliant .sup.1H NMR.
MS: [M+H]=342
2. Synthesis of Compound 59 According to the Invention
##STR00242##
With a procedure similar to that described for example 52,
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
isobutyl(4-trifluoromethylphenyl)amide (178 mg; 40%) is obtained in
the form of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.84 (d, J=6.6 Hz, 6H), 1.22-1.51
(m, 5H), 2.07-2.24 (m, 1H), 3.23 (td, J=11.4, 2.9 Hz, 2H), 3.42 (d,
J=7.3 Hz, 2H), 3.81 (ddd, J=11.6, 4.2, 2.1 Hz, 2H), 4.37 (d, J=7.1
Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.43 (dd, J=8.9, 1.8 Hz, 1H), 7.73
(d, J=8.6 Hz, 2H), 7.91 (d, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.31 (d,
J=1.0 Hz, 1H).
MS: [M+H]=496
Example 54: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(2-cyano-4-methylphenyl)isobutylamide
##STR00243##
1. Synthesis of Intermediate 54.1
##STR00244##
1H-indazole-5-sulfonic acid
(2-cyano-4-methylphenyl)amide
With a procedure similar to that described for intermediate 53.1,
1H-indazole-5-sulfonic acid (2-cyano-4-methylphenyl)amide (342.4
mg; 100%) is obtained in the form of a yellowish solid with a
compliant .sup.1H NMR.
MS: [M+H]=313
2. Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(2-cyano-4-methylphenyl)isobutylamide (compound 70)
With a procedure similar to that described for example 52,
1-(tetrahydropyran-4-ylmethyl)-2H-indazole-5-sulfonic acid
(2-cyano-4-methylphenyl)isobutylamide (129.7 mg; 20%) is obtained
in the form of a white solid.
.sup.1H NMR (Chloroform-d) .delta.: 0.93 (d, J=6.7 Hz, 6H),
1.42-1.53 (m, 4H), 1.54-1.67 (m, 1H), 2.21-2.39 (m, 1H), 2.42 (s,
3H), 3.37 (td, J=11.3, 3.5 Hz, 2H), 3.45 (d, J=7.2 Hz, 2H), 3.98
(dt, J=11.7, 2.6 Hz, 2H), 4.32 (d, J=7.2 Hz, 2H), 7.25 (d, J=8.2
Hz, 1H), 7.41 (dd, J=8.2, 2.1 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.52
(d, J=8.9 Hz, 1H), 7.78 (dd, J=8.9, 1.6 Hz, 1H), 8.15 (d, J=1.0 Hz,
1H), 8.18 (d, J=1.6 Hz, 1H).
MS: [M+H]=467
Example 55: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4,6-dimethylpyridin-3-yl)isobutylamide
##STR00245##
1. Synthesis of Intermediate 55.1
##STR00246##
1H-indazole-5-sulfonic acid
(4,6-dimethylpyridin-3-yl)amide
With a procedure similar to that described for intermediate 53.1,
1H-indazole-5-sulfonic acid (4,6-dimethylpyridin-3-yl)amide (151
mg; 46%) is obtained in the form of a yellowish solid with a
compliant .sup.1H NMR.
MS: [M+H]=303
2. Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4,6-dimethylpyridin-3-yl)isobutylamide
With a procedure similar to that described for example 52,
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4,6-dimethylpyridin-3-yl)isobutylamide (17 mg; 7%) is obtained in
the form of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.78 (d, J=6.7 Hz, 3H), 0.95 (d,
J=6.6 Hz, 3H), 1.18-1.56 (m, 5H), 2.13-2.27 (m, 4H), 2.41 (s, 3H),
3.19-3.29 (m, 3H), 3.44 (dd, J=13.3, 8.6 Hz, 1H), 3.78-3.89 (m,
2H), 4.40 (d, J=7.0 Hz, 2H), 7.21 (s, 1H), 7.56 (dd, J=8.9, 1.8 Hz,
1H), 7.68 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H),
8.33 (s, 1H).
MS: [M+H]=457
Example 56: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-dimethylaminophenyl)isobutylamide
##STR00247##
1. Synthesis of Intermediate 56.1
##STR00248##
1H-indazole-5-sulfonic acid
(4-dimethylaminophenyl)amide
With a procedure similar to that described for intermediate 53.1,
1H-indazole-5-sulfonic acid (4-dimethylaminophenyl)amide (281 mg;
81%) is obtained in the form of a fluffy white solid with a
compliant .sup.1H NMR.
MS: [M+H]=317
2. Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-dimethylaminophenyl)isobutylamide (compound 72)
##STR00249##
With a procedure similar to that described for example 52,
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-dimethylaminophenyl)isobutylamide (19 mg; 4%) is obtained in the
form of a white solid.
.sup.1H 1H NMR (Chloroform-d) .delta.: 0.94 (d, J=6.7 Hz, 6H),
1.38-1.55 (m, 3H), 1.62 (dd, J=13.2, 6.3 Hz, 2H), 2.31 (dt, J=11.0,
5.6 Hz, 1H), 2.97 (s, 6H), 3.30 (d, J=7.3 Hz, 2H), 3.38 (td,
J=11.3, 3.1 Hz, 2H), 3.99 (ddd, J=11.7, 4.4, 2.1 Hz, 2H), 4.31 (d,
J=7.1 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 6.84-6.91 (m, 2H), 7.41-7.46
(m, 1H), 7.60 (dd, J=8.9, 1.6 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 8.11
(d, J=0.9 Hz, 1H).
MS: [M+H]=471
Example 57: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(2-fluoro-4-methylphenyl)isobutylamide
##STR00250##
1. Synthesis of Intermediate 57.1
##STR00251##
1H-indazole-5-sulfonic acid
(2-fluoro-4-methylphenyl)amide
With a procedure similar to that described for intermediate 53.1,
1H-indazole-5-sulfonic acid (2-fluoro-4-methylphenyl)amide (189 mg;
94%) is obtained in the form of a yellowish solid with a compliant
.sup.1H NMR.
MS: [M+H]=306
2. Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(2-fluoro-4-methylphenyl)isobutylamide
With a procedure similar to that described for example 52,
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(2-fluoro-4-methylphenyl)isobutylamide (19 mg; 4%) is obtained in
the form of a white solid.
.sup.1H 1H NMR (Chloroform-d) .delta.: 0.93 (d, J=6.6 Hz, 6H), 1.47
(td, J=11.2, 10.7, 4.2 Hz, 3H), 1.54-1.69 (m, 2H), 2.30 (dd,
J=10.7, 4.6 Hz, 1H), 2.36 (s, 3H), 3.24-3.47 (m, 5H), 3.95-4.03 (m,
2H), 4.31 (d, J=7.1 Hz, 2H), 6.82 (dd, J=11.5, 1.8 Hz, 1H), 6.94
(dd, J=8.2, 1.8 Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.45 (dt, J=9.0,
0.9 Hz, 1H), 7.67 (dd, J=8.9, 1.6 Hz, 1H), 8.13 (dd, J=9.3, 1.2 Hz,
2H).
MS: [M+H]=460
Part II: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme
2
##STR00252##
Example 58: Synthesis of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)oxetan-3-ylmethylamide
##STR00253##
1. Synthesis of Intermediate 58.1
##STR00254##
2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol
A mixture of 4-ethylaniline (513 .mu.l; 4.13 mmol),
oxetane-3-carbaldehyde (807.3 mg; 3.75 mmol) and tetrahydrofuran
(2.5 ml) is stirred for 2 hours at room temperature. Sodium
triacetoxyborohydride (1.19 g; 5.63 mmol) is added and the reaction
medium is stirred for 16 hours at room temperature, hydrolyzed and
extracted with ethyl acetate.
The organic phases are combined, washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The
2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol (340 mg; 40%) is
obtained in the form of an orange oil with a .sup.1H NMR showing
the opening of the oxetane.
MS: [M+H]=228
2. Synthesis of Intermediate 58.2
##STR00255##
2-chloromethyl-3-(4-ethylphenylamino)propan-1-ol
A mixture of 1H-indazole-5-sulfonyl chloride (368.5 mg; 1.62 mmol),
pyridine (3.0 ml; 37.17 mmol) and
(4-ethylphenyl)oxetan-3-ylmethylamine (340 mg; 1.78 mmol) is
stirred for 30 minutes at a temperature of 100.degree. C. under
microwave irradiation.
The reaction medium is diluted with ethyl acetate. The organic
phase is washed with saturated ammonium chloride solution, with
saturated sodium hydrogen carbonate solution and with water. It is
dried (MgSO.sub.4), filtered and concentrated to dryness.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The
1H-indazole-5-sulfonic acid
(2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (260 mg; 39%)
is obtained in the form of a colorless oil with a compliant .sup.1H
NMR.
MS: [M+H]=408
3. Synthesis of Intermediate 58.3
##STR00256##
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide
A mixture of 1H-indazole-5-sulfonic acid
(2-chloromethyl-3-hydroxypropyl)(4-ethylphenyl)amide (1.26 g; 0.64
mmol), cesium carbonate (0.31 mg; 0.96 mmol) and
4-(bromomethyl)tetrahydropyran (100 .mu.l; 0.76 mmol) in
N-methyl-2-pyrrolidone (4 ml) is stirred for 1 hour at a
temperature of 80.degree. C. The reaction medium is diluted with
ethyl acetate (20 ml).
The organic phase is washed with saturated NH.sub.4Cl solution,
with saturated NaHCO.sub.3 solution and with water. The organic
phase is dried (MgSO.sub.4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 31%)
is obtained in the form of a colorless oil. .sup.1H NMR (DMSO-d6)
.delta.: 1.18 (t, J=7.6 Hz, 3H), 1.25-1.43 (m, 4H), 1.73 (p, J=6.4
Hz, 1H), 2.61 (q, J=7.6 Hz, 2H), 3.23 (td, J=11.3, 3.0 Hz, 2H),
3.35-3.41 (m, 1H), 3.46-3.52 (m, 1H), 3.52-3.63 (m, 2H), 3.69 (qd,
J=10.8, 4.9 Hz, 2H), 3.82 (ddd, J=11.4, 4.3, 2.2 Hz, 2H), 4.39 (d,
J=7.0 Hz, 2H), 4.69 (t, J=5.1 Hz, 1H), 6.95-7.02 (m, 2H), 7.16-7.22
(m, 2H), 7.44 (dd, J=9.0, 1.8 Hz, 1H), 7.92 (d, J=8.9 Hz, 1H), 8.10
(d, J=1.6 Hz, 1H), 8.31 (s, 1H)
MS: [M+H]=506
4. Synthesis of Compound 16 According to the Invention
##STR00257##
60% sodium hydride (17.4 mg; 0.43 mmol) is added to a solution of
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(3-chloro-2-hydroxymethylpropyl)(4-ethylphenyl)amide (100 mg; 0.20
mmol) in tetrahydrofuran (3 ml). The reaction medium is stirred for
1 hour at a temperature of 80.degree. C. and then for 16 hours at a
temperature of 30.degree. C.
The reaction medium is diluted with ethyl acetate (20 ml). The
organic phase is washed with saturated NH.sub.4Cl solution (20 ml),
with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml).
The organic phase is dried (MgSO.sub.4), filtered and
concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)oxetan-3-ylmethylamide (35.0 mg; 33%) is obtained in
the form of a white solid.
.sup.1H NMR (Methanol-d4) .delta.: 1.20 (t, J=7.6 Hz, 3H),
1.31-1.51 (m, 5H), 2.27 (tq, J=10.6, 6.2, 5.6 Hz, 1H), 2.62 (q,
J=7.6 Hz, 2H), 3.01 (hept, J=7.3 Hz, 1H), 3.31-3.43 (m, 2H), 3.92
(d, J=7.7 Hz, 3H), 4.33-4.42 (m, 3H), 4.56-4.66 (m, 2H), 6.88 (d,
J=8.2 Hz, 2H), 6.93-7.03 (m, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.58 (dd,
J=8.9, 1.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 8.13 (s, 1H)
MS: [M+H]=470
Part III: Synthesis of the Bicyclic Sulfonamides Via Reaction
Scheme 3
##STR00258##
Example 59: Synthesis of methyl
5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-in-
dazole-7-carboxylate
##STR00259##
1. Synthesis of Intermediate 59.1
##STR00260##
methyl
5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate
(4-Ethylphenyl)isobutylamine (417.5 mg; 2.35 mmol) is added to
methyl 5-chlorosulfonyl-1H-indazole-7-carboxylate (300 mg; 1.07
mmol) in acetonitrile (4 ml). The reaction medium is stirred for 1
hour 20 minutes at a temperature of 100.degree. C. under microwave
irradiation.
The reaction medium is diluted with ethyl acetate, washed with 1N
hydrochloric acid solution, and then with saturated sodium hydrogen
carbonate solution and with water, dried (MgSO.sub.4), filtered and
concentrated.
The methyl
5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate
(429.8 mg; 97%) is obtained in the form of a white solid with a
compliant .sup.1H NMR.
MS: [M+H]=416
2. Synthesis of methyl
5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-in-
dazole-7-carboxylate (compound 74)
##STR00261##
4-(Bromomethyl)tetrahydropyran (97.6 .mu.l; 0.74 mmol) is added to
a mixture of methyl
5-[(4-ethylphenyl)isobutylsulfamoyl]-1H-indazole-7-carboxylate
(280.0 mg; 0.67 mmol) and cesium carbonate (329 mg; 1 mmol) in
1-methyl-2-pyrrolidone (2.8 ml). The reaction medium is stirred at
a temperature of 80.degree. C. overnight.
The crude product is filtered and then purified by preparative HPLC
(C18 column, eluent: acetonitrile in water/0.1% of formic acid).
The methyl
5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-in-
dazole-7-carboxylate (223.4 mg; 63%) is obtained in the form of a
white solid.
NMR (DMSO-d6) .delta.: 0.85 (d, J=6.6 Hz, 6H), 1.18 (t, J=7.6 Hz,
3H), 1.25 (dt, J=11.1, 5.3 Hz, 4H), 1.33-1.55 (m, 1H), 1.86-2.12
(m, 1H), 2.60 (q, J=7.6 Hz, 2H), 3.18 (td, J=11.1, 3.6 Hz, 2H),
3.35 (s, 2H), 3.79 (dt, J=11.4, 3.3 Hz, 2H), 3.93 (s, 3H), 4.57 (d,
J=7.2 Hz, 2H), 6.93-7.06 (m, 2H), 7.12-7.23 (m, 2H), 7.80 (d, J=1.7
Hz, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.48 (s, 1H)
MS: [M+H]=514
Example 60: Synthesis of
5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-in-
dazole-7-carboxylic acid amide
##STR00262##
Aqueous ammonia (1.05 ml) is added to a solution of methyl
5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-in-
dazole-7-carboxylate (210.0 mg; 0.41 mmol) in N,N-dimethylformamide
(1.05 ml).
The reaction medium is stirred for 3 days at room temperature and
for 2 days at a temperature of 60.degree. C. The reaction medium is
diluted and extracted with dichloromethane. The organic phases are
combined, dried (MgSO.sub.4), filtered and concentrated to
dryness.
The crude product is filtered and then purified by preparative HPLC
(C18 column, eluent: acetonitrile in water/0.2% of ammonium
carbonate). The
5-[(4-ethylphenyl)isobutylsulfamoyl]-1-(tetrahydropyran-4-ylmethyl)-1H-in-
dazole-7-carboxylic amide is obtained in the form of a white
solid.
.sup.1H NMR (Chloroform-d) .delta.: 0.94 (d, J=6.7 Hz, 6H), 1.25
(t, J=7.6 Hz, 3H), 1.38-1.51 (m, 4H), 1.59-1.69 (m, 1H), 2.08-2.21
(m, 1H), 2.67 (q, J=7.6 Hz, 2H), 3.25-3.39 (m, 4H), 3.90-4.01 (m,
2H), 4.59 (d, J=7.2 Hz, 2H), 5.75 (s, 1H), 6.00 (s, 1H), 6.94-7.00
(m, 2H), 7.11-7.18 (m, 2H), 7.62 (d, J=1.7 Hz, 1H), 8.15 (d, J=1.6
Hz, 1H), 8.19 (s, 1H) MS: [M+H]=499
Part IV: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme
4
##STR00263##
Example 61: Synthesis of
N-(4-ethylphenyl)-N-isobutyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-inda-
zole-5-sulfonamide
##STR00264##
1. Synthesis of Intermediate 60.1
##STR00265##
3-bromo-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide
N-Bromosuccinimide (120 mg; 0.67 mmol) is added to a solution of
1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide (200 mg;
0.56 mmol) in dichloromethane (5 ml). The reaction medium is
stirred for 16 hours at room temperature, diluted with
dichloromethane and extracted.
The organic phase is washed with saturated NH.sub.4Cl solution,
with saturated NaHCO.sub.3 solution and with water, dried
(MgSO.sub.4), filtered and concentrated to dryness.
The 3-bromo-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide (260 mg; 100%) is obtained in the form
of a pale yellow solid with a compliant .sup.1H NMR.
MS: [M+H]=436
2. Synthesis of Intermediate 60.2
##STR00266##
3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide
A mixture of 3-bromo-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide (260 mg; 0.60 mmol), cesium carbonate
(388 mg; 1.19 mmol) and 4-(bromomethyl)tetrahydropyran (160 mg;
0.89 mmol) in N-methyl-2-pyrrolidone (3 ml) is stirred for 1 hour
at a temperature of 80.degree. C.
The reaction medium is diluted with ethyl acetate (30 ml). The
organic phase is washed with saturated NH.sub.4Cl solution (20 ml),
with saturated NaHCO.sub.3 solution (20 ml) and with water (20 ml),
dried (MgSO.sub.4), filtered and concentrated to dryness.
The 3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic
acid (4-ethylphenyl)isobutylamide (350 mg; 100%) is obtained in the
form of a clear yellow oil with a compliant .sup.1H NMR.
MS: [M+H]=534
3. Synthesis of Compound 14 According to the Invention
##STR00267##
2.5 M n-Butyllithium (900 .mu.l; 2.24 mmol) is added, under argon,
to a solution of
3-bromo-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide (200 mg; 0.37 mmol) in tetrahydrofuran
(3 ml) at a temperature of -78.degree. C. The reaction medium is
stirred for 30 minutes, paraformaldehyde (980 mg; 2.24 mmol) is
then added, the temperature is allowed to return to room
temperature and the medium is then stirred for 3 hours at a
temperature of 60.degree. C.
The reaction medium is hydrolyzed with 1M hydrochloric acid
solution (5 ml) at room temperature for 10 days, and diluted with
ethyl acetate (50 ml).
The organic phase is washed with saturated NH.sub.4Cl solution (20
ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20
ml), dried (MgSO.sub.4), filtered and concentrated to dryness.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
3-hydroxymethyl-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic
acid (4-ethylphenyl)isobutylamide (20 mg; 11%) is obtained in the
form of a colorless oil.
.sup.1H NMR (CD3OD-d4) .delta.: 0.90 (d, J=6.7 Hz, 7H), 1.22 (t,
J=7.6 Hz, 3H), 1.27-1.58 (m, 4H), 1.71 (d, J=12.7 Hz, 2H), 2.16 (s,
1H), 2.64 (q, J=7.7 Hz, 2H), 3.35 (s, 2H), 3.41 (t, J=11.6 Hz, 2H),
3.96 (dd, J=11.9, 4.1 Hz, 2H), 4.66 (s, 2H), 6.92 (d, J=9.0 Hz,
1H), 7.00 (d, J=7.9 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.6
Hz, 1H), 8.03 (d, J=2.4 Hz, 1H)
MS: [M+H]=486
Part V: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme
5
##STR00268##
Example 62: Synthesis of 3-amino-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00269##
1. Synthesis of Intermediate 61.1
##STR00270##
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid
A solution of (4-ethylphenyl)isobutylamine (0.80 g; 4.51 mmol) and
pyridine (0.36 ml; 4.51 mmol) in tetrahydrofuran (8 ml) is added to
a solution of 5-chlorosulfonyl-2-fluorobenzoic acid (1.44 g; 5.87
mmol) in tetrahydrofuran (8 ml).
The reaction medium is stirred for 19 hours at room temperature,
hydrolyzed with aqueous 1N HCl solution and diluted with ethyl
acetate.
The organic phase is washed with aqueous 1N HCl solution. The
organic phase is dried (Na.sub.2SO.sub.4), filtered and
concentrated.
The crude product is chromatographed on silica gel (eluent:
dichloromethane/methanol, from 0 to 10% of methanol) and then by
preparative HPLC (C18 column, eluent: from 60% to 70% of
acetonitrile in water/0.1% of formic acid). The
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic acid (0.56 g;
33%) is obtained in the form of an off-white solid with a compliant
.sup.1H NMR.
MS: [M-H]=378
2. Synthesis of Intermediate 61.2
##STR00271##
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic
A solution of 5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoic
acid (0.59 g; 1.55 mmol) in thionyl chloride (5.0 ml) is stirred
for 3 hours at reflux and then concentrated to dryness. The
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.62
g; 100%) is obtained in the form of a brown oil.
MS: [M-H]=397
3. Synthesis of Intermediate 61.3
##STR00272##
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide
A 0.5M solution of ammonia in dioxane (8.4 ml; 4.2 mmol) is added
portionwise over a period of 43 hours to a solution of
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzoyl chloride (0.31
g; 0.78 mmol) in tetrahydrofuran (3 ml). The reaction medium is
hydrolyzed with aqueous NaHCO.sub.3 solution and extracted with
ethyl acetate.
The extracted organic phase is washed with 1N sodium hydroxide,
dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude
product is chromatographed on silica gel (eluent: heptane/ethyl
acetate, from 20 to 50% of ethyl acetate). The
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g;
58%) is obtained in the form of a white solid with a compliant
.sup.1H NMR.
MS: [M-H]=379
4. Synthesis of Intermediate 61.4
##STR00273##
3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide
Triethylamine (0.19 ml; 1.35 mmol) and then trifluoroacetic
anhydride (93 .mu.l; 0.67 mmol) are added to a solution of
5-[(4-ethylphenyl)isobutylsulfamoyl]-2-fluorobenzamide (0.17 g;
0.45 mmol) at 0.degree. C. The reaction medium is stirred for 1
hour, hydrolyzed for 15 minutes and extracted with ethyl acetate.
The organic phases are combined, dried (Na.sub.2SO.sub.4), filtered
and concentrated.
The 3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide
(0.17 g; 89%) is obtained in the form of a white solid (HPLC
purity=85%) with a compliant .sup.1H NMR.
MS: [M-H]=361
5. Synthesis of Compound 34 According to the Invention
##STR00274##
Hydrazine hydrate (1.25 ml; 25.7 mmol) is added to a suspension of
3-cyano-N-(4-ethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide
(0.19 g; 0.45 mmol) in ethanol (2.5 ml). The reaction medium is
stirred for 50 minutes at a temperature of 100.degree. C. in a
tube. The reaction medium is concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.2% of ammonium carbonate). The
3-amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide
(78 mg; 53%) is obtained in the form of a solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t,
J=7.5 Hz, 3H), 1.34-1.48 (m, 1H), 2.59 (q, J=7.7 Hz, 2H), 3.28-3.32
(m, 2H), 5.73 (s, 2H), 6.96 (d, J=7.8 Hz, 2H), 7.16 (d, J=7.8 Hz,
2H), 7.26 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 8.19 (s, 1H),
11.91 (s, 1H).
MS: [M-H]=373
Example 63: Synthesis of 3-amino-1H-indazole-5-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00275##
3-Amino-1H-indazole-5-sulfonic acid (4-ethylphenyl)isobutylamide
(54 mg; 0.14 mmol) in dimethyl sulfoxide (0.80 ml) is added to
potassium hydroxide (29 mg; 0.44 mmol) at 85% in dimethyl sulfoxide
(0.20 ml). The reaction medium is stirred for 5 minutes and
4-(bromomethyl)tetrahydropyran (27 mg; 0.15 mmol) in dimethyl
sulfoxide (0.50 ml) is then added. Stirring is continued for 3
hours 20 minutes, followed by hydrolysis with a few drops of water
and filtration through a filter syringe. The filtrate is purified
by preparative HPLC (C18 column, eluent: acetonitrile in water/0.1%
of formic acid).
The 3-amino-1-(tetrahydropyran-4-ylmethyl)-1H-indazole-5-sulfonic
acid (4-ethylphenyl)isobutylamide (30 mg; 44%) is obtained in the
form of a colorless oil.
.sup.1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.6 Hz, 6H), 1.17 (t,
J=7.6 Hz, 3H), 1.21-1.47 (m, 5H), 2.59 (q, J=7.6 Hz, 2H), 3.23 (td,
J=11.5, 2.4 Hz, 2H), 3.77-3.88 (m, 2H), 4.03 (d, J=7.0 Hz, 2H),
6.92-7.01 (m, 2H), 7.16 (d, J=8.3 Hz, 2H), 7.26 (dd, J=8.9, 1.8 Hz,
1H), 7.51 (d, J=8.9 Hz, 1H), 8.17 (d, J=1.7 Hz, 1H).
MS: [M-H]=471
Part VI: Synthesis of the Bicyclic Sulfonamides Via Reaction Scheme
6
##STR00276##
Example 64: Synthesis of
3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00277##
1. Synthesis of Intermediate 63.1
##STR00278##
1H-Indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
A mixture of 1H-indazole-6-sulfonyl chloride (500 mg; 2.31 mmol),
pyridine (3 ml) and (4-ethylphenyl)oxetan-3-ylmethylamine (491 mg;
2.77 mmol) is stirred for 30 minutes at a temperature of 50.degree.
C. The reaction medium is diluted with ethyl acetate.
The organic phase is washed with saturated NH.sub.4Cl solution,
with saturated NaHCO.sub.3 solution and with water. It is dried
over magnesium sulfate, filtered and concentrated to dryness.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 40% of ethyl acetate). The
1H-Indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (640 mg;
78%) is obtained in the form of a colorless oil and is obtained
with a compliant .sup.1H NMR.
MS: [M+H]=358
2. Synthesis of Intermediate 63.2
##STR00279##
3-bromo-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
N-Bromosuccinimide (956 mg; 5.37 mmol) is added to a solution of
1H-indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (1.60 g;
4.48 mmol) in dichloromethane (10 ml). The reaction medium is
stirred for 16 hours at room temperature and diluted with
dichloromethane.
The organic phase is extracted and washed with saturated ammonium
chloride solution, with saturated sodium hydrogen carbonate
solution and with water. It is dried (MgSO.sub.4), filtered and
concentrated to dryness. The 3-bromo-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (1.9 g; 97%) is obtained in the form
of a pale yellow solid with a compliant .sup.1H NMR.
MS: [M+H]=436
3. Synthesis of Intermediate 63.3
##STR00280##
3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
A mixture of 3-bromo-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (700 mg; 1.60 mmol), pyridinium
p-toluenesulfonate (202 mg; 0.80 mmol) and 3,4-dihydro-2H-pyran
(0.58 ml; 6.42 mmol) in tetrahydrofuran (10 ml) is stirred for 16
hours at 80.degree. C. The reaction medium is diluted with ethyl
acetate (20 ml) and extracted.
The organic phase is washed with saturated NH.sub.4Cl solution,
with saturated NaHCO.sub.3 solution and with water, dried
(MgSO.sub.4), filtered and concentrated to dryness.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (500 mg; 57%) is obtained in the form
of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.86 (dd, J=13.3, 6.7 Hz, 6H), 1.18
(t, J=7.6 Hz, 3H), 1.38-1.63 (m, 3H), 1.68-1.81 (m, 1H), 1.98 (d,
J=10.7 Hz, 2H), 2.60 (q, J=7.6 Hz, 2H), 3.36-3.41 (m, 2H),
3.67-3.76 (m, 1H), 6.00 (dd, J=9.3, 2.4 Hz, 1H), 6.95-7.02 (m, 2H),
7.16-7.21 (m, 2H), 7.41 (dd, J=8.5, 1.4 Hz, 1H), 7.83 (d, J=8.8 Hz,
1H), 7.99 (s, 1H)
MS: [M+H]=520
4. Synthesis of Intermediate 63.4
##STR00281##
1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-
-sulfonic acid (4-ethylphenyl)isobutylamide
A mixture of p-toluenesulfonyl hydrazide (286 mg; 1.54 mmol),
4-formyltetrahydropyran (175 mg; 1.54 mmol) and 1,4-dioxane (2 ml)
is stirred for 1 hour under argon. Lithium tert-butoxide (125 mg;
1.54 mmol), X-PHOS (18 mg; 0.04 mmol),
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (40 mg;
0.04 mmol) and
3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (200 mg; 0.38 mmol) are added under
argon, and the reaction medium is stirred for 5 hours at
100.degree. C.
The reaction medium is diluted with 20 ml of ethyl acetate and
extracted. The organic phase is washed with saturated NH.sub.4Cl
solution (20 ml), with saturated NaHCO.sub.3 solution (20 ml) and
with water (20 ml), dried (MgSO.sub.4), filtered and
concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 100% of ethyl acetate).
The
1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indaz-
ole-6-sulfonic acid (4-ethylphenyl)isobutylamide (100 mg; 48%) is
obtained in the form of a yellow oil with a compliant .sup.1H
NMR.
MS: [M+H]=538
5. Synthesis of Compound 62 According to the Invention
##STR00282##
A mixture of
1-(tetrahydropyran-2-yl)-3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole--
6-sulfonic acid (4-ethylphenyl)isobutylamide (100 mg; 0.19 mmol),
acetic acid (6 ml) and water (2 ml) is stirred for 5 hours at a
temperature of 80.degree. C. The reaction medium is diluted with 20
ml of ethyl acetate and extracted. The organic phase is washed with
saturated NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3
solution (20 ml) and with water (20 ml), dried (MgSO.sub.4),
filtered and concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The
3-(tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (80 mg; 93%) is obtained in the form
of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.7 Hz, 7H), 1.17 (t,
J=7.6 Hz, 3H), 1.41 (dt, J=13.6, 6.8 Hz, 1H), 2.60 (q, J=7.3 Hz,
2H), 2.93 (t, J=5.4 Hz, 2H), 3.65 (t, J=5.5 Hz, 2H), 3.73 (t, J=5.4
Hz, 2H), 6.61 (s, 1H), 6.95 (d, J=8.3 Hz, 2H), 7.13-7.21 (m, 2H),
7.22 (dd, J=8.5, 1.5 Hz, 1H), 7.63-7.67 (m, 1H), 7.98 (d, J=8.5 Hz,
1H).
MS: [M+H]=454
Example 65: Synthesis of
3-(tetrahydropyran-4-ylmethyl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00283##
3-(Tetrahydropyran-4-ylidenemethyl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (60 mg; 0.13 mmol) in methanol (3 ml)
in the presence of palladium (5% Pd on activated charcoal: Degussa
type) (14 mg) is placed for 16 hours under hydrogen (1 atm). The
reaction medium is filtered through Celite. The filtrate is
concentrated to dryness. The crude product is chromatographed on
silica gel (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl
acetate). The 3-(tetrahydropyran-4-ylmethyl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide (30 mg; 50%) is obtained in the
form of a white solid.
.sup.1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.4 Hz, 6H), 1.17 (t,
J=7.6 Hz, 3H), 1.23-1.48 (m, 3H), 1.56 (d, J=13.4 Hz, 2H), 1.97 (d,
J=11.7 Hz, 1H), 2.56-2.65 (m, 2H), 2.90 (d, J=7.0 Hz, 2H), 3.26 (t,
J=11.3 Hz, 2H), 3.82 (dd, J=11.6, 3.8 Hz, 2H), 6.97 (d, J=8.1 Hz,
2H), 7.19 (dd, J=14.2, 8.2 Hz, 3H), 7.62 (s, 1H), 7.95 (d, J=8.3
Hz, 1H), 13.15 (s, 1H).
MS: [M+H]=456
Part VII: Synthesis of the Bicyclic Sulfonamides Via Reaction
Scheme 7
##STR00284##
Example 65: Synthesis of
3-morpholin-4-ylmethyl-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00285##
1. Synthesis of Intermediate 65.1
##STR00286##
1-(tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
Bis(tri-t-butylphosphine)palladium(0) (49 mg; 0.10 mmol) is added
to a mixture, degassed under argon, of
3-bromo-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (500 mg; 0.96 mmol), cesium carbonate
(940 mg; 2.88 mmol) and vinylboronic anhydride-pyridine complex
(462 mg; 1.92 mmol) in 1,4-dioxane (3 ml) and water (1 ml).
The reaction medium is stirred for 3 hours at a temperature of
90.degree. C. and filtered through Celite. The filtrate is diluted
with ethyl acetate and extracted.
The organic phase is washed with 20 ml of saturated sodium hydrogen
carbonate solution and with 20 ml of water. The organic phase is
washed with saturated NH.sub.4Cl solution (20 ml), with saturated
NaHCO.sub.3 solution (20 ml) and with water (20 ml), dried
(MgSO.sub.4), filtered and concentrated.
The crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 100% of ethyl acetate). The
1-(tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (400 mg; 89%) is obtained in the form
of a beige-colored solid with a compliant .sup.1H NMR.
MS: [M+H]=468
2. Synthesis of Intermediate 65.2
##STR00287##
3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide
1-(Tetrahydropyran-2-yl)-3-vinyl-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (400 mg; 0.86 mmol) is added to a
mixture of (DHQ).sub.2PHAL (1.20 g; 1.46 mmol), tert-butyl alcohol
(10 ml) and water (10 ml) cooled to a temperature of 0.degree. C.
The reaction medium is stirred for 16 hours at a temperature of
40.degree. C. Sodium sulfite (5 g) is added.
The reaction medium is stirred for 45 minutes, diluted with ethyl
acetate (30 ml) and extracted. The organic phases are combined,
washed with saturated Na.sub.2SO.sub.3 solution (20 ml) and with
water (20 ml), dried (MgSO.sub.4), filtered and concentrated. The
crude product is chromatographed on silica gel (eluent:
heptane/ethyl acetate, from 0 to 100% of ethyl acetate).
The
3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfoni-
c acid (4-ethylphenyl)isobutylamide (380 mg; 89%) is obtained in
the form of a clear oil with a compliant .sup.1H NMR.
MS: [M+H]=502
3. Synthesis of Intermediate 65.3
##STR00288##
3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
Sodium metaperiodate (1.62 g; 7.58 mmol) is added to a mixture of
3-(1,2-dihydroxyethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide (380 mg; 0.76 mmol), acetone (2
ml), tetrahydrofuran (2 ml) and water (2 ml).
The reaction medium is stirred for 2 hours 30 minutes at a
temperature of 35.degree. C., diluted with ethyl acetate (30 ml)
and water (20 ml) and extracted.
The organic phases are combined, washed with saturated
Na.sub.2SO.sub.3 solution (20 ml) and with water (20 ml), dried
(MgSO.sub.4), filtered and concentrated. The
3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (120 mg; 34%) is obtained in the form
of a white solid with a compliant .sup.1H NMR.
MS: [M+H]=470
4. Synthesis of Intermediate 65.4
##STR00289##
3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide
Morpholine (45 .mu.l; 0.51 mmol) and sodium triacetoxyborohydride
(119 mg; 0.56 mmol) are added to a solution of
3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (120 mg; 0.26 mmol) in tetrahydrofuran
(3 ml). The reaction medium is stirred for 2 hours at room
temperature. The reaction medium is diluted with ethyl acetate (20
ml) and water (10 ml) and extracted.
The organic phase is washed with saturated NH.sub.4Cl solution (20
ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20
ml), dried (MgSO.sub.4) and concentrated.
The
3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfoni-
c acid (4-ethylphenyl)isobutylamide (130 mg; 94%) is obtained in
the form of an oil with a compliant .sup.1H NMR.
MS: [M+H]=541
5. Synthesis of Compound 64 According to the Invention
##STR00290##
A mixture of
3-morpholin-4-ylmethyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide (130 mg; 0.24 mmol), acetic acid
(30 ml) and water (10 ml) and a few drops of trifluoroacetic acid
is stirred for 4 days at a temperature of 80.degree. C. The
reaction medium is diluted with 50 ml of ethyl acetate and
extracted.
The organic phase is washed with saturated NH.sub.4Cl solution (20
ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20
ml), dried (MgSO.sub.4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
3-morpholin-4-ylmethyl-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (70 mg; 64%) is obtained in the form
of a white solid after recrystallization from an acetone/water
mixture.
1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.7 Hz, 6H), 1.18 (t, J=7.6
Hz, 3H), 2.44 (t, J=4.5 Hz, 4H), 2.61 (t, J=7.6 Hz, 2H), 3.33-3.37
(m, 2H), 3.87 (s, 2H), 6.95-7.00 (m, 2H), 7.15-7.21 (m, 2H), 7.25
(dd, J=8.5, 1.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 13.27 (s, 1H).
MS: [M+H]=457
Example 66: Synthesis of
3-((cis)-2,6-dimethylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide
##STR00291##
1. Synthesis of Intermediate 66.1
##STR00292##
3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-i-
ndazole-6-sulfonic acid (4-ethylphenyl)isobutylamide
cis-2,6-Dimethylmorpholine (50 .mu.l; 0.38 mmol) and sodium
triacetoxyborohydride (122 mg; 0.57 mmol) are added to a solution
of 3-formyl-1-(tetrahydropyran-2-yl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (90 mg; 0.19 mmol) in tetrahydrofuran
(2 ml).
The reaction medium is stirred for 16 hours at room temperature.
The reaction medium is diluted with ethyl acetate (20 ml) and water
(10 ml) and extracted. The organic phase is washed with saturated
NH.sub.4Cl solution (20 ml), with saturated NaHCO.sub.3 solution
(20 ml) and with water (20 ml), dried (MgSO.sub.4) and
concentrated. The
3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H--
indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 83%)
is obtained in the form of an oil with a compliant .sup.1H NMR.
MS: [M+H]=570
2. Synthesis of Compound 65 According to the Invention
##STR00293##
A mixture of
3-((2S,6R)-2,6-dimethylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H--
indazole-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 0.16
mmol), acetic acid (10 ml) and water (10 ml) and one drop of
trifluoroacetic acid is stirred for 16 hours at a temperature of
80.degree. C. The reaction medium is diluted with 50 ml of ethyl
acetate and extracted.
The organic phase is washed with saturated NH.sub.4Cl solution (20
ml), with saturated NaHCO.sub.3 solution (20 ml) and with water (20
ml), dried (MgSO.sub.4), filtered and concentrated.
The crude product is purified by preparative HPLC (C18 column,
eluent: acetonitrile in water/0.1% of formic acid). The
3-((cis)-2,6-dimethylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic
acid (4-ethylphenyl)isobutylamide (52 mg; 67%) is obtained in the
form of a colorless oil.
1H NMR (DMSO-d6) .delta.: 0.85 (d, J=6.5 Hz, 6H), 1.02 (d, J=6.1
Hz, 6H), 1.18 (t, J=7.5 Hz, 3H), 1.42 (dt, J=13.3, 7.1 Hz, 1H),
1.74 (t, J=10.7 Hz, 2H), 2.55-2.65 (m, 2H), 2.70-2.80 (m, 2H),
3.33-3.44 (m, 2H), 3.55 (t, J=7.8 Hz, 2H), 3.85 (s, 2H), 6.98 (d,
J=8.0 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.66
(s, 1H), 8.03 (d, J=8.6 Hz, 1H), 8.20 (s, 1H), 13.25 (s, 1H).
MS: [M+H]=485
Example 67: Synthesis of
3-((S)-3-methylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide
##STR00294##
1. Synthesis of Intermediate 67.1
##STR00295##
3-((S)-3-methylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole--
6-sulfonic acid (4-ethylphenyl)isobutylamide
With a procedure similar to that described for intermediate 67.1,
3-((S)-3-methylmorpholin-4-ylmethyl)-1-(tetrahydropyran-2-yl)-1H-indazole-
-6-sulfonic acid (4-ethylphenyl)isobutylamide (90 mg; 85%) is
obtained in the form of an oil with a compliant .sup.1H NMR.
MS: [M+H]=555
2. Synthesis of Compound 66 According to the Invention
With a procedure similar to that described for example 66,
3-((S)-3-methylmorpholin-4-ylmethyl)-1H-indazole-6-sulfonic acid
(4-ethylphenyl)isobutylamide (42 mg; 54%) is obtained in the form
of a colorless oil.
1H NMR (DMSO-d6) .delta.: 0.86 (d, J=6.8 Hz, 6H), 1.09-1.22 (m,
7H), 1.42 (dt, J=13.9, 6.9 Hz, 1H), 2.16-2.27 (m, 1H), 2.61 (t,
J=7.6 Hz, 2H), 3.38 (d, J=19.0 Hz, 5H), 3.58-3.72 (m, 3H), 6.98 (d,
J=7.9 Hz, 2H), 7.18 (d, J=7.9 Hz, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.65
(s, 1H), 8.04 (d, J=8.6 Hz, 1H), 8.24 (s, 1H), 13.24 (s, 1H).
MS: [M+H]=471
* * * * *